MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Terapie a podpůrné vlivy ke zvrácení jaterní steatózy

2,4-dinitrophenol

  • mitochondrial uncoupler
  • Potential in treating nonalcoholic fatty liver disease (NAFLD)
  • Improved metabolic symptoms in two diet-induced nonhuman primate models of NAFLD
  • Controlled-release mitochondrial protonophore (CRMP)
    • Improved insulin resistance, dyslipidemia, and hepatic steatosis in nonhuman primates treated over the course of 6 weeks
    • Without increases in oxidative stress, liver enzymes, or adverse events.
  • Preclinical study supports further work to translate CRMP for the treatment of metabolic diseases in humans
  • www.science.org/doi/10.1126/scitranslmed.aay0284

Mitochondrial uncouplers - 2,4-dinitrophenol (DNP)

  • Shuttle protons across the inner mitochondrial membrane
    • Via a pathway that is independent of adenosine triphosphate (ATP) synthase
      • Uncoupling nutrient oxidation from ATP production
  • DNP has been known to increase metabolic rates since the late 1800s
  • Effective and widely used weight loss drug in the 1930s
  • Chronic ingestion of DNP is associated with
    • Including fatal hyperthermia and death
      • Banned by the U.S. Food and Drug Administration (FDA) in 1938

Modified forms of DNP

Rodent models of NAFLD, NASH, and T2D


Semaglutid

  • Nedavno doběhlá studie - dobrý efekt na snížení statozy jater

ACEIs and ARBs

  • Block the effects of angiotensin II
  • Commonly prescribed to treat high blood pressure and HF
  • ACEIs and ARBs may have beneficial effects on NAFLD
  • Angiotensin II is a key contributor to abnormal lipid metabolism in NAFLD
  • Angiotensin II can
    • Worsen insulin sensitivity,
    • Generate ROS,
    • Trigger the production of inflammatory cytokines
      • TNF-a, IL-6, and PAI-1,
        • Contribute to NAFLD progression
  • Retrospective cohort study of over 12000 patients with NAFLD
    • Treatment with ACEIs for at least six months
    • Associated with a lower risk of liver cancer and cirrhosis
  • This effect was not seen with ARBs[42]. These data are surprising for
  • Enjoji et al showed that ARBs can
    • Restore intracellular insulin signaling
    • Facilitate the movement of excess fat from non-adipose tissues to adipocytes
      • May improve markers of liver function such as transaminases, hepatic steatosis, and inflammation
  • Several clinical trials and meta-analyses have suggested that ACEIs and ARBs
    • Effective in reducing mortality and hospitalization in patients with HFrEF and Advanced Kidney Disease
use of BB and/or RASi at hospital discharge was associated with lower 30-d and 1-year mortality rates, even among patients aged > 85 years[51]. Similarly, the CHARM-

Bariatric surgery

  • Described in the context of liver defatting.
  • One group reported the case of an obese patient who donated a liver lobe for transplantation after undergoing sleeve gastrectomy with positive results
  • Might represent a possible option in the future.
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext

Ablation of hormone-sensitive lipase (Hsl) in mice


ACEI and ARB

  • HFrEF Reduced liver-related events, liver cancer, and cirrhosis complications[47] Placebo Cohort
  • HFrEF Trial failed to evidence that losartan 50 mg has antifibrotic effects on NASH due to widespread use
  • Patients with CKD-NAFLD taking ACEI or ARB
    • Had significantly lower liver stiffness degrees in comparison to those without those drugs
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/
  • Block the effects of angiotensin II
  • Commonly prescribed to treat high blood pressure and HF
  • ACEIs and ARBs may have beneficial effects on NAFLD
  • Angiotensin II is a key contributor to abnormal lipid metabolism in NAFLD
  • Angiotensin II can
    • Worsen insulin sensitivity,
    • Generate ROS,
    • Trigger the production of inflammatory cytokines
      • TNF-a, IL-6, and PAI-1,
        • Contribute to NAFLD progression
  • Retrospective cohort study of over 12000 patients with NAFLD
    • Treatment with ACEIs for at least six months
    • Associated with a lower risk of liver cancer and cirrhosis
  • This effect was not seen with ARBs[42]. These data are surprising for
  • Enjoji et al showed that ARBs can
    • Restore intracellular insulin signaling
    • Facilitate the movement of excess fat from non-adipose tissues to adipocytes
      • May improve markers of liver function such as transaminases, hepatic steatosis, and inflammation
  • Several clinical trials and meta-analyses have suggested that ACEIs and ARBs
    • Effective in reducing mortality and hospitalization in patients with HFrEF and Advanced Kidney Disease
use of BB and/or RASi at hospital discharge was associated with lower 30-d and 1-year mortality rates, even among patients aged > 85 years[51]. Similarly, the CHARM-

Aescin and diosmin

Diosmin randomized, controlled study evaluating diosmin tablets administered daily for 3 months.


Aktivace SIRT1

  • Important roles in a variety of processes, including
    • Energy homeostasis
    • Liver function,
    • Protective effects in obesity and metabolic disorders (Nguyen et al., 2020)
  • Low serum levels of SIRT1 linked to
    • Elevation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha
    • Acetylation of nuclear factor kappaB
    • Leading to inflammation in patients with type 2 diabetes mellitus (Kitada et al., 2011)
  • SIRT1 expression and activity
    • Decline with weight gain,
    • Likely associated with the dysregulation of the NAD+/SIRT pathway expression in obese patients
      • Can lead to other conditions, such as
        • Inflammation, insulin resistance, impaired insulin homeostasis, and liver steatosis (Jukarainen et al., 2016).
  • Its role in downregulating sterol response element-binding protein 1c
    • Key activator of de novo lipogenesis in the liver
  • SIRT1 triggers beta-oxidation in hepatocytes
    • Limiting weight gain and preventing obesity (Liou et al., 2019)
  • Colak et al. (2014) also demonstrated that the activation of SIRT1 improves NAFLD.
  • Downregulation of SIRT1
    • Can augment fatty liver and inflammation
    • Lower SIRT1 levels have been reported in obese patients with NAFLD (Mariani et al., 2015)
  • SIRT1 mRNA levels in visceral and subcutaneous adipose tissues
    • Were reduced in obese women compared with normal-weight women (Song et al., 2013).
  • Lack of SIRT1 activity
    • Can lead to liver steatosis in animal models
  • SIRT1 should be considered a potential therapeutic target of NAFLD.

"Sirtuin diet" "Sirt diet"

  • Top sirtfoods
  • Kale
  • Red wine
  • Strawberries
  • Onions
  • Soy
  • Parsley
  • Extra virgin olive oil
  • Dark chocolate (85% cocoa)
  • Matcha green tea
  • Buckwheat
  • Turmeric
  • Walnuts
  • Arugula (rocket)
  • Bird’s eye chili
  • Lovage
  • Medjool dates
  • Red chicory
  • Blueberries
  • Capers
  • Coffee

Synthetic and natural/dietary aldose reductase (AR) inhibitors


Alpha-Lipoic Acid

  • Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. Diabetologia, 1995. DOI: 10.1007/bf00400603
  • Alpha-lipoic acid prevents non-alcoholic fatty liver disease in OLETF rats

Effect of Vitamin E and Alpha Lipoic Acid in Nonalcoholic Fatty Liver Disease: A Randomized, Placebo-Controlled, Open-Label, Prospective Clinical Trial (VAIN Trial)

Double-blind, placebo-controlled randomized clinical trial with two parallel groups

  • Fifty patients with NAFLD
    • Daily supplementation with either two capsules of alpha-LA (each capsule containing 600 mg alpha-LA)
    • Or two placebo capsules, daily for 12 weeks
  • All participants received consultation on how to implement a healthy diet into their daily lives
  • A significant reduction was observed in the serum levels of insulin (P = 0.024) and leptin (P = 0.019) in the alpha-LA group
    • Compared to the placebo group,
  • Anthropometric and body composition measures, serum glucose (FSG), resistin, irisin and liver enzymes
    • Did not differ between the groups
  • Alpha-LA supplementation resulted in a statistically significant
    • Elevation in the quantitative insulin sensitivity check index (QUICKI) (P = 0.033),
    • Serum levels of adiponectin (P = 0.008)
    • adiponectin-to-leptin ratio (P = 0.007) compared to the placebo.
  • Liver steatosis intensity improved significantly.
    • no significant differences were observed between the study groups in the liver steatosis intensity, at the end of the study.
  • pubs.rsc.org/en/content/articlelanding/2019/fo/c9fo00449a

Amino acid catabolites

  • Regulatory role in NAFLD
    • By influencing intestinal epithelial barrier
    • Therapeutic effects on liver function
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]


Amlodipine, lisinopril and rosuvastatin


Higher consumption of animal organ meat

  • Is associated with a lower prevalence of nonalcoholic steatohepatitis

The 136 participants (80.9% men) of the study

  • Prevalence of definite NASH was 65.4%.
  • Daily median organ meat consumption was 1.30 g/1,000 kcal.
  • Animal organ meat consumption was inversely associated with the presence of NASH
    • Even after adjustment of demographics, lifestyle variables, metabolic and dietary factors, as well as liver fibrosis stage
  • Adjusted-odds ratios (95% confidence intervals) for NASH were
    • 0.15 (0.03, 0.69) for the highest tertile
    • 0.18 (0.05, 0.70) for the medium tertile
    • Compared to the lowest (reference) tertile of animal organ meat intake (P value for trend =0.024).
  • Our results suggest for the first time that higher animal organ meat consumption
    • Is associated with a lower prevalence of NASH in Chinese individuals with biopsy-proven NAFLD.
  • pubmed.ncbi.nlm.nih.gov/37886189/

Anthocyanins

  • water-soluble pigments of
    • Coloured berries,
    • Fruits
    • Vegetables
  • Can protect hepatocytes against injury caused by high glucose-induced oxidative damage,
    • By improving antioxidant status
    • Inhibiting the mitochondria pathways of apoptosis
  • Prevention of hyperglycemia-induced mitochondrial depolarization
    • Helps mitochondria to maintain their function
  • Treatment with anthocyanins
    • Increases mitochondrial fatty acid oxidation
      • Via activation of genes participating in this metabolic pathway
        • PPARg, PPARa, UCP-2, UCP-3 and mitochondrial transcription factor A
  • Can attenuate mitochondrial defects caused by inhibition of complex I in human and rat tissues
  • In isolated mitochondria from ischemic hearts
    • Anthocyanins were found to recover complex I activity
      • Enhancing the rate of ATP synthesis
  • A normal functioning of respiratory complex I is necessary to ensuring mitochondrial ATP synthesis and its supply to cells
  • Inhibition of complex I
    • Results in a decrease of oxidative phosphorylation
  • Anthocyanins can act as electron acceptors in a similar way as endogenous coenzyme Q.
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm

Antibiotics

  • Can eliminate harmful microbiota
  • Efficacy has been confirmed in various liver diseases

Neomycin, metronidazole, rifaximin, and polymyxin B

  • For treating cirrhosis and hepatic encephalopathy

Polymyxin B and neomycin

  • Prevented lipid accumulation in the liver by altering the gut microbiota

Short-term administration of antibiotics

  • Improved the clinical symptoms in NAFLD/NASH patients
  • By lowering circulating endotoxins
  • Lowered serum transaminases

Rifaximin

  • Significant reduction of transaminase and NAFLD-liver fat score

Clinical trial conducted by Ponziani et al rifaximin

  • Showed little therapeutic effects against NASH
  • Discrepancy could be the result of low drug dose, short duration of the treatment, and small sample size.
  • Antibiotic-induced changes in the gut microbiota
    • Can provide valuable insights into its therapeutic utility in various diseases
  • Specific antibiotics can positively affect the gut microbiota
    • By promoting the growth of beneficial gut bacteria like
      • Bifidobacteria and Lactobacilli.
  • Short-term antibiotic treatment may have a therapeutic effect
  • Long-term application
    • Can lead to the emergence of bacterial resistance
      • Limiting the efficacy of the drug
      • Increasing the risk of secondary infections
  • Chronic antibiotic use is not encouraged
    • Can affect the beneficial gut bacteria and cause intestinal dysbiosis
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]


Apple cider vinegar

  • Rich source of acetic acid, a naturally occurring acid that has been found to support healthy blood sugar regulation and increases cellular sensitivity to insulin, which prevents the conversion of blood sugar into fatty acids and reduces fat storage in liver cells.
  • www.drberg.com/blog/how-to-reverse-a-fatty-liver


Aramchol, an SCD-1 inhibitor

  • Cholic acid-arachidic acid conjugate

Double-blind, placebo-controlled trial of 60 patients with biopsy-proven NAFLD

  • (only 6 had NASH)
  • Daily 100 mg or 300 mg Aramchol vs. placebo (n = 20 per group)for 3 months
  • Drug was associated with
    • Reduced hepatic fat content when administered as a 300 mg/day regimen vs. placebo

Multicenter phase IIb trial


Artichoke (Cynara scolymus):

  • Adzet T, Camarasa J, Laguna JC. Hepatoprotective activity of polyphenolic compounds from Cynara scolymus against CCl4 toxicity in isolated rat hepatocytes. Journal of Natural Products, 1987. DOI: 10.1021/np50087a013
  • Artichoke leaf, from the plant Cynara scolymus
    • Demonstrated hepatoprotective, antimicrobial and cholesterol-lowering actions
    • Antioxidant activity through decreased production of reactive oxygen species
    • Decreased lipid peroxidation
    • Increased activity of glutathione peroxidase

60 patients with NASH trial

  • Cynara scolymus extract (6 tablets/day for a total of 2700mg extract/day)
  • Or placebo (6 tablets/day) for two months + life style advice both groups
  • Both groups experienced a significant reduction from baseline
    • Mean body weight,
    • Serum levels of AST and ALT.
  • Supplementation with C. scolymus resulted in
    • Significant reduction in blood sugar, TC, LDL and TGs.
    • Levels of liver enzymes, TGs and TC were significantly reduced compared to the placebo group
  • Higher improvement in liver enzymes and also lipid profile following administration of C. scolymus
    • In comparison to placebo in multivariate regression analyses
  • go.gale.com/ps/i.do?p=AONE&u=googlescholar&id=GALE|A473692810&v=2.1&it=r&sid=AONE&asid=1c9d9eaf

Astaxanthin

  • Xanthophyll carotenoid
  • In various marine organisms, such as
    • Yeast,
    • Salmon,
    • Shrimp,
    • Crayfish
    • Green microalga Haematococcus pluvialis
  • Well demonstrated that this carotenoid has strong antioxidant properties
  • 100-fold to 500-fold more effective than vitamin E in preventing lipid peroxidation and in reducing lipid accumulation in liver
  • In mice models astaxanthin can
    • Down-regulate genes involved in lipogenesis and lipid-uptake
    • Without influencing fatty acid oxidation-related genes in the liver
  • Reduce hepatic levels of TGs and cholesterol in mice
  • Astaxantin in improvement of mitochondrial function
  • Increase mitochondrial membrane potential and respiratory control
    • Important measures of mitochondrial health
    • Increase in mitochondrial respiration efficiency observed in astaxanthin-treated cells
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm
  • Astaxanthin is also present in krill oil,
    • A dietary source of n-3 long-chain PUFAs
    • Reducing liver lipids were more pronounced than that found with fish oil-fed rats
  • Astaxanthin induces fatty acid catabolism
    • By activation of Acyl-CoA oxidase (ACOX1) - target gene of PPAR
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm


BCAA supplementation

  • Under conditions of insulin sensitivity
    • Improved the feeding-to-fasting induction of hepatic lipid oxidation
      • Through changes in cellular redox
        • Providing a favorable biochemical environment for flux through beta-oxidation
        • Lower de novo lipogenesis
  • Branched-chain amino acids (BCAAs)
    • Modulate lipid metabolic networks in various tissues
      • Especially during insulin resistance
  • Supplementation of BCAAs to normal, insulin-sensitive mice resulted in higher
  • This change in the cellular redox status provided an optimal metabolic milieu to
    • Increase fatty acid oxidation
    • Keeping the rates of de novo lipogenesis lower in the BCAA-supplemented mice livers.
  • pubmed.ncbi.nlm.nih.gov/36791321/

  • BCAA and related metabolites
    • Among the strongest biomarkers of
      • Obesity,
      • Insulin resistance,
      • T2D,
      • Cardiovascular diseases
  • Tedy markery ztráty a odbourávání svaloviny ev. katabolismu proteinů.
  • Lowering of BCAA and branched-chain ketoacid (BCKA) levels
    • By feeding BCAA-restricted diet
    • By the activation of the rate-limiting enzyme in BCAA catabolism
      • Branched-chain ketoacid dehydrogenase (BCKDH)
      • In rodent models of obesity
    • Clear salutary effects on glucose and lipid homeostasis
  • Pokud je model ve stavu, kdy svaly ztrácí a katablizuje BCAA, jejich přidáním rozhodně neřešíme příčinu, jen zvyšujeme vznikající nerovnováhu.
  • Restrikce BCAA může přechodně vzniklou nerovnováhu upravit.
  • BCAA restriction
    • Modest effects in short-term studies in human T2D subjects
  • Feeding of rats with diets enriched in sucrose or fructose
    • Result in the induction of the ChREBP transcription factor in the liver
      • To increase expression of the BCKDH kinase (BDK)
      • Suppress the expression of its phosphatase (PPM1K)
      • Resulting in the inactivation of BCKDH
      • Activation of the key lipogenic enzyme ATP-citrate lyase (ACLY)


Berberine - BBR

Kong et al., 2004 [45] RCT adult hypercholesterolemic patients,

  • N = 63 1 g/1 day (BBR hydrochloride),
  • 3 months
  • Lower ALT, AST, GGT, TC, TG, LDL-c

Xie et al., 2011 [46] RCT adult NAFLD and 2 diabetes patients;

  • N = 60 0.3 g/1 day (BBR),
  • 12 weeks
  • Lower TG, TC, LDL, ALT lower liver lipid content

Bai et al., 2011 [47] RCT adult NAFLD patients,

  • N = 68 0.5 g/1 day (BBR + metformin)
  • 3 months
  • Lower of level of FPG, TC, TG, LDL-C, FINS, HOMA-IR, ^ adiponectin, lower IR

Marazzi et al., 2011 [48] RCT elderly hypercholesterolemic patients,

  • N = 80 0.5 g/1 day (BBR + policosanol 10 mg, red yeast rice 200 mg, folic acid 0.2 mg, coenzyme Q10 2.0 mg, and astaxanthin 0.5 mg), 12 months
  • Lower TC, LDL-C, IR

Di Pierro et al., 2012 [49] RCT adult 2 diabetes patients;

  • N = 22 0.588 g/1 day (Berberol®, B. aristata extract titered as 85% berberine and 105 mg of S. marianum extract titered as >60% flavonolignans),
  • 90 days
  • Lower HbA1c, TC, LDL-C, HDL-C, T, FR, BMI, HOMA-IR

Cao et al., 2012 [50] RCT adult NAFLD patients,

  • N = 78 0.5 g/1 day (BBR + metformin)
  • 16 weeks
  • Lower HOMA-IR, TC, TG, LDL, ALT, AST, 2hPG

Pérez-Rubio et al., 2013 [51] RCT adult MetS patients, - n = 24 1.5 g/1 day (berberine hydrochloride),

  • 3 months
  • Lower SBP, waist circumference, TG, and total insulin secretion.
  • Lower waist circumference in females, SBP, TG, area under the curve (AUC) of glucose, AUC of insulin and insulinogenic index.

Ning et al., 2013 [52] RCT adult NAFLD patients;

  • N = 44 0.5 g/1 day (BBR + metformin),
  • 16 weeks
  • Lower HbA1C, TC, TG

Manzato & Benvenut, 2014 [53] RCT adult dyslipidemic patients,

  • N = 1161 0.5 g/1 day BBR + ed yeast rice extract 200 mg (equivalent to 3 mg monacolins), policosanol 10 mg, 0.2 mg folic acid, coenzyme Q10 2 mg, and asthaxantin 0.5 mg (Armolipid Plus, Rottapharm|Madaus) with or without diet,
  • 16 weeks
  • Lower TC, LDL-C, TG

Li, 2015 [54] RCT adult NAFLD patients,

  • N = 96 0.3 g/1 day (BBR),
  • 3 months
  • Lower 2hPG, HbA1C, TC, LDL, ALT, AST

Yan H-M. et al., 2015 [55] RCT adult NAFLD patients,

  • N = 184 1.5 g/1 day (BBR),
  • 16 weeks
  • Lower hepatic fat content, ALT, AST, y-GT, glucose, HOMA-IR, TC, TG, LDL-c

Wang et al., 2016 [56] RCT adult mild hyperlipemia patients,

  • N = 97 0.3 g/1 day (vs. 0.9 g/1 day),
  • 3 months
  • Lower TG, TC i LDL-C, ^ HDL-C

Xinxia Chang et al., 2016 [24] RCT adult NAFLD patients,

A meta-analysis of 27 randomized controlled trials (RCTs) on BBR

  • no profound adverse effects during T2D, hyperlipidemia, or hypertension treatment.
  • BBR in these trials were at a relatively low cost compared with other first-line medicines and therapies

A meta-analysis of 21 clinical trials

  • BBR is effective in the treatment of T2D, hyperlipidemia, and hypertension, in comparison with other therapeutic options
  • Because MAFLD conception is gaining more attentio
  • Effect of BBR on NAFLD might be more effective if more studies with longer terms were included.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC9459907/



Berberine

  • Zhang H, Wei J, Xue R, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism, 2010. DOI: 10.1016/j.metabol.2009.07.029
  • Pleiotropic effect positively impacts various cardiometabolic aspects
  • Hepatoprotective effects of BBR due to its broad spectrum of pharmacological effects
    • Potential role of BBR in NAFLD therapy.
  • BBR ameliorates NAFLD by affecting numerous abnormalities
    • It inhibits lipogenesis and gluconeogenesis
    • Improves insulin resistance and lipid profile
    • Modulates gut microbiota
  • Speculate about the importance of this natural bioactive substance for NAFLD therapy
  • BBR is an isoquinoline alkaloid
  • Initially isolated from the root and rhizome of the herb Coptis chinensis
  • In traditional Chinese Medicine to treat diarrhea and many infectious gastrointestinal disorders for over 3000 years.
  • Bioactive constituent in the roots, rhizomes, stem, and barks of many medicinally plants
    • Hydrasti scanadensis (goldenseal),
    • Berberis vulgaris (barberry),
    • Berberis aquifolium (Oregon grape),
    • Coptis chinensis (Coptis or goldenthread)
    • Berberis aristata (Tree turmeric)
  • BBR is currently produced by the process of chemical synthesis.
  • Chloride or sulfate salt of BBR is widely used in clinical practice.
    • Intense yellow powder with no smell
    • Characteristic alkaloidal bitter taste
  • Very low toxicity in usual doses
  • Clinically beneficial with the absence of significant side effects
  • Only reported adverse effects were mild gastrointestinal reactions that rarely occurred

Multiple studies confirmed the positive role of BBR in

  • Preventing CV and metabolic disorders such as NAFLD and T2D
  • Option for improving NAFLD and its complications
  • Broad spectrum of pharmacological effects
    • Crucial antihypertensive, antihyperglycemic, antioxidant, anti-inflammatory, and hypolipidemic activity
  • Various studies present the
    • Nephroprotective, hepatoprotective, and cardioprotective potential of BBR
  • BBR has been used as a non-prescription drug to treat
    • Diarrhea, stomatitis, dysentery, and hepatitis
  • Numerous studies have been conducted to investigate
    • On T2D, lipid metabolism, and tumors
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC9459907/

Betaine

  • Increases hepatic S-adenosylmethionine [1]

Bile acid (BA)

  • cholesterol derivative that is synthesized and conjugated in the liver
  • Central role in digestion by emulsifying dietary fats
  • Promoting the absorption of lipids and vitamins in the small intestine (mainly the ileum)
  • BA is a critical signaling molecule - connects the intestine and liver

BA receptor (BAR) - known as FXR

  • Highly expressed in the liver and intestine
  • Regulates the synthesis of bile acids through a feedback mechanism
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]


Phytotherapy using blueberry leaf polyphenols

  • To alleviate non-alcoholic fatty liver disease through improving mitochondrial function and oxidative defense
  • PBL effectively alleviated hepatic steatosis, oxidative stress and inflammation as indicated by both in vitro and in vivo study.
  • PBL mediated improvement of mitochondrial dysfunction and antioxidant capability through activation of AMPK/PGC-1?/SIRT3 signaling axis.
Zheng Li 1, Huixia Zhang 1, Yan Li 1, Hongwei Chen 2, Caiyun Wang 1, Vincent Kam Wai Wong 1, Zhihong Jiang 1, Wei Zhang 3 PMID: 32240928 DOI: 10.1016/
j.phymed.2020.153209

Blueberry Juice + Probiotics


Camelina sativa oil - CSO supplementation

Triple-blind, placebo-controlled, randomized clinical trial on 46 NAFLD patients

  • CSO supplement or placebo for 12 weeks
  • Both groups received a loss weight diet.

Results:

  • CSO supplementation for 12 weeks causes significant changes in NAFLD patients:
    • All of anthropometric indices (except hip circumference and neck circumference),
    • ALT,
    • Lipid profile (except HDL-c),
    • Atherogenic index,
    • adiponectin
  • pubmed.ncbi.nlm.nih.gov/35421019/

Caffeine:

  • Saab S, Mallam D, Cox GA 2nd, et al. Impact of coffee on liver diseases: a systematic review. Liver International, 2014. DOI: 10.1111/liv.12440

Carnosic acid (CA)

  • Protects mice from high-fat diet-induced NAFLD by regulating MARCKS
  • phenolic diterpene with anticancer, anti-bacterial, anti-diabetic and neuroprotective properties
  • Produced by many species of the Lamiaceae family

Wild-type C57BL/6 and MARCKS-deficient mice randomly divided

  • Normal chow- or high-fat (HF) diet-fed group
  • HF diet
    • Increased the fasting glucose and insulin levels
    • Promoted glucose intolerance in the wild-type mice
  • MARCKS deficiency further upregulated intolerance, fasting glucose and insulin.
  • The HF diet also promoted hepatic steatosis, ALT, AST activity, inflammation and lipid accumulation in the wild-type mice.
    • These responses were accelerated in the MARCKS-deficient mice.
  • Mice treated with CA
    • Exhibited a significantly improved glucose and insulin tolerance.
    • Pro-inflammatory cytokines and lipid accumulation were suppressed by CA
    • CA treatment upregulated MARCKS expression compared to the HF group
    • PI3K/AKT, NLRP3/NF-?B and SREBP-1c signaling pathways was inhibited by CA.
  • CA suppresses inflammation and lipogenesis in mice fed a HF diet
    • Through MARCKS regulation
  • CA may be prove to be a useful anti-NAFLD agent
  • fat-NAFLD-by-Song-Li/035b8b6f1d0bcb8895f8e934cc57f3f94c895f62">www.semanticscholar.org/paper/Carnosic-acid-protects-mice-from-high-fat-NAFLD-by-Song-Li/035b8b6f1d0bcb8895f8e934cc57f3f94c895f62

Carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol


Carotenoids

  • Lipophilic pigments responsible for the yellow, orange or red colours of flowers and fruits.
  • Scavenging activity of ROS is well known
  • Ability of beta-carotenes to be the primary dietary source of provitamin A
  • The most prevalent carotenoids in the diet are
    • Alpha- and beta-carotene, lutein, lycopene, zeaxanthin and cryptoxanthin.
  • Carotenoids accumulate mainly in the liver
    • Incorporated into lipoproteins
    • Released into the circulation in the form of lipoproteins
  • Dietary carotenoids may physiologically scavenge free radical species in the liver
    • Thus inhibiting the development of hepatic dysfunction
  • Considered potent antioxidants and antiinflammatory micronutrients
    • Prevention and treatment of NAFLD
  • Critical regulators of macrophage polarization
    • Thereby inhibit the development and the progression of NASH
  • May act through multiple mechanisms.
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm

Lycopene, astaxanthin and fucoxanthin

  • Evidence of the positive effects on the reversion of fatty liver
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm


Cenicriviroc

  • CCR2/CCR5 antagonist
  • CCL2 and CCL5 are two of 17 up-regulated genes in NASH patients

Phase IIb trial (CENTAUR) currently awaited in NASH patients.


Chitosan oligosaccharides (COS)

  • Oligosaccharide

HepG2 cells

  • Attenuates hepatic steatosis
    • Via the activation of AMP-activated protein kinase
  • Significantly increased the expression levels of fatty acid oxidation-related factors
    • Carnitine palmitoyltransferase 1A,
    • Acyl-coenzyme A oxidase 1,
    • Peroxisome proliferators-activated receptor
  • Phosphorylated AMP-activated protein kinase (AMPK)
  • Inhibition of lipogenesis
  • Enhancement of fatty acid oxidation induced by COS
    • All blocked by AMPK antagonist (compound C)
    • Attenuation of hepatic steatosis by COS was dependent on AMPK activation
  • COS attenuated hepatic steatosis via suppressing lipid synthesis and enhancing fatty acid oxidation
  • COS might be used as a potential ingredient to ameliorate nonalcoholic fatty liver disease.
  • onlinelibrary.wiley.com/doi/10.1111/jfbc.14045

C57BL/6 Mice with fatty Liver Disease Induced by High Fat Diet

  • Chitosan Oligosaccharide Attenuates Nonalcoholic fatty Liver Disease
    • Reducing Lipid Accumulation, Inflammation and Oxidative Stress
  • www.mdpi.com/1660-3397/17/11/645

High-fat diet-treated mice

Sulfate chitosan derivatives

  • Good solubility and therapeutic effect on the cell model of NAFLD

Male Wistar rats were orally fed high fat emulsion for 5 weeks

  • Followed by sulfate chitosan derivatives for 3 weeks
  • Sulfate chitosan derivatives can
    • Dramatically prevent the development of hepatic steatosis in hepatocyte cells
  • Pre-treatment and treatment with sulfate chitosan derivatives
    • Significantly protected against hepatic steatohepatitis induced by high fat diet
  • Increased TC, ALT, MDA, and LEP in NAFLD were significantly ameliorated by pre-treatment and treatment with sulfate chitosan derivatives
  • Increased TG, AST, and TNF-a in NAFLD
    • Were significantly ameliorated by treatment with sulfate chitosan derivatives
  • Sulfate chitosan derivatives have good pre-treatment and therapeutic effect on NAFLD.
  • link.springer.com/article/10.1007/s11802-014-2511-y



Choline rich food

  • The richest sources are meat, fish, poultry, dairy, eggs
  • Beef, beef liver
  • Egg yolks
  • Chicken breast
  • Fish
  • Shiitake mushrooms
  • Potatoes
  • Legumes (beans, peanuts)
  • Milk
  • Yogurt
  • Cruciferous vegetables (broccoli, cauliflower, Brussels sprouts, cabbage)
  • Sunflower seeds
  • Salmon, cod, tilapia
  • Body can make some choline on its own

Signs of Deficiency

  • choline deficiency can lead to
    • Muscle damage
    • Liver damage
    • Nonalcoholic fatty liver disease

Groups at higher risk of deficiency

  • Pregnant women
  • Intravenous nutrition
  • Digestive diseases

Toxicity of very high intakes of choline

  • Low blood pressure (hypotension)
  • Liver toxicity
  • Excess production of TMAO
    • Higher risk of cardiovascular disease
  • Excessive sweating
  • Fishy body odor
  • Or nausea/vomiting

Tolerable Upper Intake Level (UL)



Choline

  • Officially recognized as an essential nutrient by the USA Institute of Medicine in 1998
  • One of the “under-consumed” nutrients in the USA during 2015–2020
  • Dietary 2020–2025 guidelines for Americans (from Choline Science Summit held in Washington DC, 2018)
    • Recommend an adequate intake of choline for pregnant women, infants, and toddlers
  • Choline deficiency causes liver, brain, and muscle dysfunctions
    • Impairs neurocognitive development
    • Induces DNA damage and apoptosis in the lymphocytes of patients with organ dysfunctions
  • High dietary choline intake in humans
    • Maintains normal body weight and fat percentage
  • Low dietary choline intake
    • Increases liver fat
  • Consistently, mice fed with a methionine- and choline-deficient diet (MCDD) developed fatty liver
    • Such mice have been used as a model of non-alcoholic fatty liver disease (NAFLD)
  • onlinelibrary.wiley.com/doi/full/10.1002/mnfr.202000361

Chymase inhibition

  • A chymotrypsin-like enzyme
  • Produced in mast cells
  • Activation of
    • Angiotensin II,
    • Matrix metalloproteinase (MMP)-9,
    • Transforming growth factor (TGF)-b
  • Associated with oxidative stress, inflammation, and fibrosis
  • Augmentation of chymase activity in the liver in various NASH models
  • Attenuated by treatment with a chymase inhibitor
    • MMP-9
    • Accumulation of inflammatory cells
    • TGF-b and collagen I upregulation in NASH is also attenuated by chymase inhibition

Experimental NASH models

  • Chymase inhibitor can effectively ameliorate NASH
    • Via the reduction of oxidative stress, inflammation, and fibrosis

Suc-Val-Pro-Phe-P(OPh)2


Čištění si zubů

Korea National Health and Nutrition Examination Survey in 2010

  • 6,352 subjects were analyzed.
  • NAFLD was defined as fatty liver index ?60.
  • An inverse association between toothbrushing frequency and NAFLD was found.
  • ORs (95% CIs) of NALFD was 0.56 (0.35–0.91) in the group who performed toothbrushing 3 a více per day
    • Compared to the group that performed toothbrushing 1 a méně per day
  • Frequency 1 a méně per day, the adjusted OR (95% CIs) of NAFLD was
    • 2.26 (1.22–4.19) in smokers
    • 4.52 (1.97–10.38) in subjects with diabetes mellitus (DM)
    • Compared to those without the disease and with toothbrushing frequency 2 a více per day
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8158973/

Co-treatment citicoline alone and with Lactobacillus

  • Improve histopathological NASH outcomes
  • Reversed all of these molecular pathological alterations linked to NASH
    • Via upregulating the expression of Nrf2/HO-1 and downregulating TLR4/NF-kB signaling pathways.
  • Citicoline and lactobacillus may represent new hepatoprotective strategies against NASH progression.
  • pubmed.ncbi.nlm.nih.gov/37291355/

Cocktail of defatting agents: forskolin, hypericin, scoparone, visfatin and L-carnitine

  • Perfuze lidských jater před transplantací
  • Control group perfused under the same condition, without adding the cocktail
  • Grafts in the treatment group showed increased
    • Ketogenesis,
    • Solubility of the TG
    • ATP synthesis
    • Greater reduction in tissue TG levels (which declined by 38%)
    • Macrovesicular steatosis (decreased by 50% after 12 h) in the treatment group
  • During the 12 h of perfusion
    • Grafts in the treatment group showed higher lactate clearance and bile production
      • Both markers of graft viability
  • Safety data is not available for some of the drugs used in the defatting cocktail
    • For example hypericin and PPAR
    • Their toxicity in humans has not been investigated
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext

Codonopsis pilosula - Dangšen (ženšen chudých)

  • Sesquiterpene glycoside, an extract of the dried root Codonopsis pilosula
  • Common drug used in traditional Chinese medicine
  • Anti-inflammatory effects
  • Recent study provided evidence that the use of sesquiterpene glycosides in mice
    • Could protect against NAFLD in patients with T2DM
  • Repair of insulin signaling
  • Inhibition of cytochrome P450 2E1 (CYP2E1) and NOD-like receptor family 3 in vivo and in vitro
    • Thus, reducing oxidative stress, inflammation, and inflammatory cytokines and preventing insulin resistance
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Cordyceps sinensis

  • Koh JH, Kim JM, Chang UJ, Suh HJ. Hypocholesterolemic effect of hot-water extract from mycelia of Cordyceps sinensis. Biological & Pharmaceutical Bulletin, 2003. DOI: 10.1248/bpb.26.849

Coumestrol

  • Coumestan
  • Natural organic compound present in some plants
    • Alfalfa,
    • Legumes,
    • Brussels sprouts,
    • Spinach,
    • Clover
    • Soybeans
  • Coumestrol induces an increase in mitochondria number and function, by activating SIRT1
  • Appears to be able to increase cellular ATP levels and glucose uptake
    • Improving energy metabolism at the same time
  • Coumestrol stimulation has been shown to augment the protein expression of respiratory chain components
    • NADH dehydrogenase 1 subcomplex 9 (NDUFA9)
    • Succinate dehydrogenase complex subunit A (SDHA)
    • Ubiquinol cytochrome c reductase core protein 2 (UQCRC2)
    • Cytochrome oxidase subunit 1 (COX1)
    • ATP synthase mitochondria F1 complex subunit 1 (ATP5a)
    • Transcriptional regulators that are responsible for mitochondrial biogenesis
  • Decrease the mRNA expression of lipogenic genes in adipocytes and hepatocytes
  • Increase fatty acid oxidation in myocytes
  • SIRT1 and AMPK might reciprocally activate each other
    • AMPK enhances SIRT1 activity by increasing cellular NAD+ levels
    • SIRT1 mediates the deacetylation of liver kinase B1 (an upstream regulator of AMPK)
      • Thereby assembling a positive feedback loop that serves to enhance energy catabolism
  • Coumestrol might activate AMPK
    • Itself a regulator of SIRT1
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm


Increase cruciferous vegetables

  • Including kale, parsley, mustard greens, and Brussels Sprouts, support liver health in several ways.
  • “Sulforaphane, a naturally active isothiocyanate compound from cruciferous vegetables used in clinical trials for cancer treatment, was found to possess the potency to alleviate insulin resistance.”
  • www.drberg.com/blog/how-to-reverse-a-fatty-liver



Curcumin

  • [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione]
  • Yellow polyphenol isolated from the rhizome of Curcuma longa
    • Used as a spice and traditional medicine in Asia for centuries
  • Antioxidant, antiinflammatory, antimutagenic, antimicrobial and anticancer properties.
  • Protect against mitochondrial dysfunction in several experimental models
  • curcumin has been reported to increase oxygen consumption and respiratory chain complexes’ activities
    • To prevent oxidative stress
    • To restore ATP content
  • Improvement in mitochondrial function was also shown to be associated with prevention against the decrease in the activity of aconitase
    • An oxidative stress marker
  • curcumin facilitated beta-oxidation in in vitro experiments
    • By up-regulation of CPT-1
    • Reducing lipogenesis at the same time
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm

Dieta + cvičení + statiny

  • Restricted calorie intake pod 1,600 kcal/day diet + exercise 3 times a week for nad 20 min + statins if hyperlipidaemia
  • Potential donors diagnosed with fatty liver via CT scan
  • The weight reduction period was 35 to 109 days
  • Control group included patients with no signs of fatty liver via imaging
  • After transplantation, there were no significant differences between the treatment group and the control group
    • In terms of patient and graft survival, early graft function and ascites volume.
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext

Cvičení

A review of studies published in 2021 in Frontiers in Nutrition

  • Regular exercise improved NAFLD?, even in patients who didn’t lose weight.
  • Elped prevent early-stage NAFLD from progressing to NASH.

Combination of strength training and cardio

  • Is most effective
  • 2-3 strength-training sessions a week
  • 150 to 300 minutes per week of moderate?-to?-vigorous aerobic activity
    • Like brisk walking, running or swimming.

Cardio is more effective


Dandelion greens

  • Choleretic and stimulate the production and flow of bile needed to digest and absorb fats.
  • Bile salts are also crucial for normal fat metabolism in the liver, and a bile deficiency can significantly increase the risk of fatty liver disease.
  • www.drberg.com/blog/how-to-reverse-a-fatty-liver

Dandelion (Taraxacum officinale):

  • Clare BA, Conroy RS, Spelman K. The diuretic effect in human subjects of an extract of Taraxacum officinale folium over a single day. Journal of Alternative and Complementary Medicine, 2009. DOI: 10.1089/acm.2008.0152

Sodium-glucose co-transporter-2 inhibitor - dapagliflozin

  • Improves liver steatosis in patients with type 2 diabetes and NAFLD
  • Attenuates liver fibrosis
    • Only in patients with significant liver fibrosis
  • ALT and GMT levels decreased in the dapagliflozin group
    • Not in the control group
  • Visceral fat mass was significantly reduced in the dapagliflozin group
  • pubmed.ncbi.nlm.nih.gov/30178600/

Dieta bez fruktozy a lačnící den

  • Reversion to regular diet (vyřazení fruktozy) with alternate day fasting

Mice high-fructose-intake-associated metabolic syndrome


Diosgenin (DG)

  • Attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPAR?/CD36 pathway
  • Natural compound extracted from Chinese herbal medicine
  • Very effective in preventing metabolic diseases

Sprague-Dawley (SD) rats induced by a high-fat diet (HFD) and in HepG2 cells exposed to free fatty acids (sodium oleate:sodium palmitate = 2:1).

  • DG treatment efficiently managed hepatic lipid deposition in vivo and in vitro.
  • DG upregulated the expression of
    • FXR
    • Small heterodimer partner (SHP)
  • Downregulated
    • Expression of genes involved in hepatic de novo lipogenesis (DNL),
      • Sterol regulatory element-binding protein 1C (SREBP1C),
      • Acetyl-CoA carboxylase 1 (ACC1),
      • Fatty acid synthase (FASN).
  • DG promoted the expression of peroxisome proliferator-activated receptor alpha
  • DG inhibited the expression of the CD36 molecule (CD36) related to fatty acid uptake
  • DG has a good effect on alleviating nonalcoholic hepatic steatosis
    • Via the hepatic FXR-SHP-SREBP1C/PPAR?/CD36 pathway.
  • pubmed.ncbi.nlm.nih.gov/37263401/

Diosmin

  • ANTI-FIBROTIC EFFECT OF DIOSMIN AGAINST DMN-INDUCED LIVER FIBROSIS IN RATS : A BIOCHEMICAL ANALYSIS
T. DevakiJohn BinuclaraSubramanian RaghunandakumarS. AsokkumarC. NaveenkumarT. Premkumar Biology, Medicine 2017

Male C57BL/6 mice fed a high-fat high-sucrose (HFHS) diet for 12 weeks

  • Diosmin significantly ameliorated dyslipidemia, by reducing TC and LDL-C levels
  • Diosmetin had little effect on these parameters
  • Diosmin and diosmetin can prevent fat accumulation and glucose intolerance
  • Diosmin was more effective and also showed an antidyslipidemic effect.
  • onlinelibrary.wiley.com/doi/pdf/10.1002/fsn3.1883

Experimental model of non-alcoholic steatohepatitis in rats




Docosahexaenoic acid-thyroid hormone protocol


Empagliflozin

  • On Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes

A Randomized, Double-Blind, Placebo-Controlled Trial

  • Significant decrease in CAP score in both groups but no significant difference was observed between the two groups (P = 0.396).
  • LSM was significantly decreased in the empagliflozin-treated group (6.03 ± 1.40 to 5.33 ± 1.08 kPa; P = 0.001)
    • no change was found in the placebo group.
  • Patients with significant steatosis at baseline (CAP ? 302 dB/m),
    • Steatosis significantly improved in the empagliflozin group (37.2% vs. 17%; P = 0.035)
  • Significant decrease in the grade of liver fat on visual analysis of ultrasound images, AST, ALT, and fasting insulin levels in the empagliflozin group,
    • While no changes were observed in the placebo group.
  • pubmed.ncbi.nlm.nih.gov/32975679/

Emricasan- pan-caspase inhibitor

  • Initially studied in patients with chronic liver diseases of diverse aetiologies
  • Found to lower ALT levels, particularly in patients with hepatitis C and with NASH

Being evaluated in a phase IIb trial in patients with NASH and fibrosis.

(ENCORE-NF; NCT02686762)

Epigallocatechin gallate

  • Ester of epigallocatechin and gallic acid
  • Flavonoid belonging to the chemical class of flavan-3-ols (catechins)
  • The most abundant catechin in green tea (Camellia sinensis L.)
    • About 50% of its total polyphenols.
  • Epigallocatechin gallate can promote fat oxidation and energy expenditure
  • At a cellular level,
    • Reduced energy uptake could activate the AMPK signalling pathway
      • May further affect energy metabolism, inducing chronic alterations in mitochondrial architecture (morphology and mass)
      • Modifications also include increase in the levels of porin and mitochondrial respiratory proteins, and in mtDNA content
  • Epigallocatechin gallate is able to modulate systemic energy use by inducing mitochondrial changes
  • Induce fatty acid beta-oxidation through an increase in mRNA levels of CPT-1 and UCP2
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm



FATP1 inhiice

Deficient mice


Farnesoid X receptor (FXR)

Mice treated with antibiotics or tempol

  • Exhibited altered bile acid composition,
  • Notable increase in conjugated bile acid metabolites
    • Inhibited intestinal farnesoid X receptor (FXR) signaling
  • Compared with control mice, animals with intestine-specific Fxr disruption had
    • Reduced hepatic triglyceride accumulation in response to a HFD
    • Decrease in hepatic triglyceride accumulation
      • Mainly due to fewer circulating ceramides
        • In part the result of lower expression of ceramide synthesis genes
  • Reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice
    • Fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis

Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD

  • Reversed hepatic steatosis

Inhibition of an intestinal FXR/ceramide axis

  • Mediates gut microbiota-associated NAFLD development
    • Linking the microbiome, nuclear receptor signaling, and NAFLD.
  • Inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment.
  • pubmed.ncbi.nlm.nih.gov/25500885/


Farnesoid X receptor (FXR)

Obeticholic acid or OCA

  • Synthetic bile acid derivative
  • FXR agonist

Recently studied in biopsy-proven NASH patients without cirrhosis in the FLINT trial

  • Multicenter, randomized, double-blind, placebo-controlled study
  • 283 patients for 72 weeks
    • Daily dose of 25 mg OCA (n = 141)
    • Placebo (n = 142)
  • In the OCA group
    • Significant histological improvement (45% vs. 21% of control; P = .0002)
    • Improved fibrosis score (35% vs. 19% of controls; P = .004)
  • Adverse effect
    • Pruritus - in OCA-treated patients (23%) leading to discontinuation in some cases
      • Reversible
    • Worsening of the lipid profile in subjects treated with OCA

Upcoming phase III trial (NCT02548351)

FGF-19

  • Hormone transcriptionally regulated via FXR activation
    • In response to the postprandial influx of bile acids in the terminal ileum
  • FGF-19 then binds to the FGFR4/beta-klotho receptor complex on the hepatocyte cell membrane
    • Suppressing gluconeogenesis
    • While promoting glycogen synthesis
  • FGFR4 activation could have a cancer-promoting effect on hepatocytes
    • Non-tumorigenic variants have been developed with some success in initial studies

NGM-282

  • Non-cancer-promoting agent

phase II trial (NCT02443116) to evaluate its effect in NASH patients over a 12-week treatment period.


Fasting



Fatty Acid Synthase inhibiton

  • To umí např. trochu omega3
  • Steatosis of alcoholic or nonalcoholic etiology
    • fat accumulation is linked to the de novo synthesis of fatty acids through FAS
  • Recent reports have shown success using FAS inhibitors to reduce the amount of liver steatosis
    • And to reduce ischemia/reperfusion injury in those livers
  • www.eurekaselect.com/article/12659

Fecal transplantation

  • Transferring functional microbiomes from the feces of healthy individuals
    • To the gastrointestinal tract of patients with intestinal dysbiosis.

Chinese medical and herbal practitioners for treating severe diarrhea and food poisoning

  • Effective therapeutic option for recurrent Clostridium difficile infection
    • As well as liver and metabolic diseases associated with intestinal microbiota dysbiosis

Clinical studies conducted so far on microbiota-targeting strategies, including FMT, in NAFLD patients

  • Several studies have demonstrated the therapeutic effects of FMT on
    • Type 2 diabetes
    • Ulcerative colitis patients
    • Associated with restored healthy microbiota, normalized blood lipid levels, and improved insulin resistance.
  • FMT is a potential therapeutic option for NAFLD and NASH as well

Le Roy et al. transplanted the feces from HFD responder and non-responder mice into germ-free recipients

  • Mice that received microbiota from the responder group developed steatosis
    • Showed a high abundance of Barnesiella and Roseburia in the intestine
  • Microbiota from the non-responder mice
    • Markedly increased the abundance of Allobaculum in the recipients
  • 8-wk FMT intervention significantly restored the disordered gut microbiota in HFD-induced NASH mouse models
    • By increasing the abundance of beneficial bacteria such as Christensen and Lactobacillus
  • Alleviated endotoxemia, liver steatosis, necrosis, and intra-hepatic inflammation
    • Compared to the untreated controls

Metabolic syndrome patients transplanted with the gut microbes of healthy individuals

  • Showed increased butyrate production
  • Improved insulin sensitivity
  • Higher abundance of beneficial bacteria in the lower gut.


Fibrates

  • Treatment of hypertriglyceridemia
  • Significant benefit in NAFLD
  • Receptor's extensive distribution in organs outside the liver

PPARdelta

  • Presence in macrophages
    • Decreasing macrophage and Kupffer cell activation and increasing fatty acid oxidation

PPARbeta/delta agonist (GW501516)

  • Highly promising in initial trials, the drug may have been withdrawn due to safety concerns

Elafibranor

  • PPARbeta/delta agonist
  • Improving both hepatic and peripheral insulin sensitivity
    • In abdominally obese individuals in a liver-targeted fashion

phase IIb, randomized double-blind placebo-controlled trial (GOLDEN-505)

  • Resolve NASH
  • Multicenter, international study with NASH patients (without cirrhosis) -3 different groups for a total of 52 weeks:
    • Placebo (n = 92)
    • Elafibranor 80 mg/day (n = 93),
    • Elafibranor 120 mg/day (n = 91):
  • Resolution of NASH
    • Significantly higher in patients with an NAFLD activity score (NAS) ?4 (n = 234) who took elafibranor 120 mg/day compared to placebo (20% vs. 11%; P = .018) - (19% vs. 9%; P = .013)
  • Regression in the stage of fibrosis
    • In the patients in whom NASH resolved with elafibranor 120 mg, compared to those in whom it did not (P < .001).
  • Liver enzymes and lipid profile
    • Improved in the 120 mg/day group.28, 29 A phase III trial (NCT02704403) is currently in the recruitment phase.
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302


Flavonoids Baicalein, silymarin, rutin, and quercetin

  • Shown hepatic protection by modulating the function of CYP2E1.
  • In fruits, vegetables, and plant-derived beverages
  • Used as nutritional supplements
  • Can improve insulin resistance, endoplasmic reticulum stress, lipid peroxidation, and fibrosis
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Forskolin

Forskolin, PPAR alpha und delta agonist, scoparone, hypericin, visfatin, amino acids

    • Faster steatosis reduction;
    • Quicker recovery of urea secretion and bile canalicular function


Short-term isocaloric fructose restriction

Jin et al. four-week randomized, controlled, double-blinded beverage intervention study

  • In 24 overweight adolescents with hepatic fat >8% on imaging
  • Calorie-matched study-provided fructose only or glucose only beverages
  • End of the study, the authors reported no significant change in hepatic fat or body weight in either group
  • Significantly improved
    • Adipose insulin sensitivity,
    • High sensitivity C-reactive protein,
    • Low-density lipoprotein oxidation in the glucose beverage group
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/

Children with NAFLD

  • Diet low in carbohydrates and sugars
  • May be more effective in
    • Reducing intrahepatic fat accumulation,
    • Insulin resistance and visceral fat
  • Compared to fat-restricted diets
  • Therefore, it is envisaged that restriction of carbohydrates, fructose, free sugars or SSB
    • Are adequate interventions to prevent NAFLD in children
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/

Fucoxanthin

  • Abundant marine carotenoids,
  • More than 10% of the estimated total carotenoids in nature
  • Xanthophyll
  • Hypolipidemic effects of fucoxanthin by
    • Down-regulation of various lipogenic enzyme activities
    • Up-regulation of fatty acid beta-oxidation activity in fat tissues
  • This carotenoid has also anti-obesity properties,
    • Stimulating UCP-1 expression in white adipose tissue
      • Usually found in brown adipose tissue and is not expressed in white adipose tissue in the absence of any stimulation
  • UCP-1 leads to heat generation (thermogenesis).
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm


GR-MD-02

  • Inhibitor of Galectin-3
    • protein expressed predominantly in immune cells
      • Recognizes and binds to galactose residues
      • Essential protein in liver fibrogenesis

2 phase II clinical trials in NASH patients with fibrosis/cirrhosis



GS-4997


Garlic powder supplementation

90 NAFLD patients were randomly for 12 weeks

  • Garlic powder supplement ( 400 mg garlic powder)
  • Placebo ( 400 mg starch)
  • Hepatic steatosis was significantly reduced in the treatment group compared with the control group (P = 0·001).
  • Significant decrease was seen
    • Alanine transaminase (P < 0·001),
    • Aspartate transaminase (P = 0·002),
    • G-glutamyltransferase (P = 0·003)
    • Total cholesterol (P = 0·009)
    • TAG (P < 0·001),
    • HDL-cholesterol (P < 0·001)
    • LDL-cholesterol (P = 0·01) in the treatment group compared with the control group
  • No significant difference in alkaline phosphatase
  • Garlic powder supplementation improved hepatic features and lipid profile among NAFLD patients.
  • pubmed.ncbi.nlm.nih.gov/32312333/

Roux-en-Y gastric bypass (RYGB)

  • Improves the pathophysiology that contributes to obesity-related nonalcoholic steatohepatitis (NASH).

106 obese adults scheduled for RYGB had preoperative liver function assessed using

  • Standard tests and ICG clearance
  • Core liver biopsies obtained during RYGB
  • Once patients lost 60% of their preoperative weight or weight loss plateaued
    • Liver function was reassessed.
    • Repeat liver biopsies were obtained on patients with NASH at the time of RYGB.

Results

  • RYGB improved steatosis, lobular inflammation, hepatocyte ballooning and fibrosis.
  • Serum albumin, AST, and ALT decreased the most in patients with NASH and NASH plus fibrosis.
  • Twenty seven (26%) patients had normal baseline liver histology
  • 45 (43%) had NASH or NASH plus fibrosis.
  • 9 of 13 patients with substantial fatty liver
    • Had normalized histology after weight loss,
  • Severity of disease in the rest had stabilized or was reduced
  • d-nb.info/1144235324/34
  • bmcobes.biomedcentral.com/articles/10.1186/s40608-017-0168-y

Genistein

  • Anti-inflammatory effect of genistein on non-alcoholic steatohepatitis rats induced by high fat diet and its potential mechanisms.

Ginger (Zingiber officinale):

  • Mansour MS, Ni YM, Roberts AL, et al. Ginger consumption enhances the thermic effect of food and promotes feelings of satiety without affecting metabolic and hormonal parameters in overweight men: A pilot study. Metabolism, 2012. DOI: 10.1016/j.metabol.2011.10.018


Ginkgo Biloba:

  • Sierpina VS, Wollschlaeger B, Blumenthal M. Ginkgo biloba. American Family Physician, 2003. PMID: 14655812

Ginseng:

  • Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. Journal of Ginseng Research, 2017. DOI: 10.1016/j.jgr.2017.04.009

Glial cell-line derived neurotrophic factor (GDNF)

  • Has been reported as another alternative strategy to reduce liver steatosis during ex vivo perfusion.
  • Initial study, Vakili et al. had determined that GDNF has a protective effect against high-fat diet (HFD)-induced hepatic steatosis
    • By reducing PPARgamma expression
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext


GLP-1 receptor agonists - exenatide and liraglutide

  • For diabetes mellitus type 2

Meta-analysis of several studies

  • Significant results in patients with NASH.
    • Decreased serum ALT levels,
    • Improvement in hepatic fat content and fibrosis
  • Associated weight loss with these medications
    • Potentially attractive for use in patients with NASH and the metabolic syndrome
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302

The LEAN study - safety and efficacy of liraglutide in NASH in 52 patients

  • 1.8 mg/day of liraglutide or placebo for 48 weeks (n = 26 in each group)
    • 39% of patients in the liraglutide group met the primary end-point
      • Resolution of NASH without worsening of fibrosis
  • Compared to 9% in the placebo group (P = .019)
  • Fibrosis only progressed in 9% of patients in the liraglutide group
    • Occurred in 36% (P = .019) of the placebo group
  • Liraglutide as one of the most attractive potential therapies available for NASH.
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302

GLP-1 receptor agonists

  • Incretin hormone secreted in the gut in response to meal ingestion
  • Increases insulin secretion
  • Inhibits glucagon production, targeting pancreatic beta-cells
  • GLP-1 receptor agonists improve hyperglycemia and delay gastric emptying
    • Promoting weight loss
  • Attractive therapeutic option for treating patients with NAFLD
    • Particularly those with associated diabetes mellitus and obesity.

Liraglutide

  • A multicenter, randomized, double-blind, placebo-controlled trial
  • Associated with the resolution of NASH with no worsening of fibrosis score
  • Improvement in steatosis, and hepatocyte ballooning score

Liraglutide and exenatide

  • Attributed to decreases in trunk fat content,
    • Especially in the android region,
      • Associated with NAFLD
      • Closely associated with CVD risk
  • Well-described effects of GLP-1
    • Augmentation of ventricular function in animals with HF or ischemia-induced ventricular dysfunction
    • Attenuation of the development or progression of atherosclerosis or plaque formation
    • Augmented myocardial or coronary artery blood flow rate control
    • Reduced blood pressure
    • Increased secretion of atrial natriuretic factor
    • Inhibition of platelet aggregation
  • GLP-1 receptor agonists
    • no effect on the risk of HF hospitalization
      • Safe to use but are not beneficial in preventing HF in at-risk patients
      • Used cautiously during acute decompensation
  • Three small randomized controlled trials of GLP-1 receptor agonists in patients with HFrEF

Liraglutide

  • LIVE and FIGHT trials studied liraglutide vs placebo
    • no changes in left ventricular ejection fraction (LVEF), quality of life, or functional class at 24 wk.

Albiglutide

  • Showed no significant differences in LVEF, BNP, 6-min walk test, myocardial glucose, or oxygen use
  • GLP-1 RAs have a positive chronotropic effect,
    • Causing an increase in heart rate
    • Induced increases in cAMP levels
      • Which may worsen HF and increase the risk of death
  • GLP-1RAs and NAFLD
    • Suggest beneficial data,
    • Observations from randomized trials suggest no clear benefit in HF-related outcomes and even uncertainty regarding safety in patients with HFrEF
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Glucagon-like peptide 1 (GLP-1)

  • Hormone that belongs to the incretin group of proteins
  • Secreted in the distal ileum and proximal colon by L cells
  • Stimulating the pancreas
    • To cause beta cell proliferation
      • Enhance insulin biosynthesis
  • GLP-1 also interacts with receptors in GI tract and in the lung, kidney and CNS
  • GLP-1 has several metabolic functions
    • Delayed gastric emptying,
    • Appetite suppression,
    • Enhanced liver glucose uptake
    • Peripheral insulin sensitivity,
    • Glucose-dependent insulin secretion
    • Inhibiting the release of glucagon
  • GLP-1 undergoes rapid degradation by the
    • Dipeptidyl peptidase 4 (DPP-4) enzyme
      • Medications are made to resist this immediate cleavage by DDP-4
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302

Glucoraphanin and sulforaphane

  • 4-methylsulfinylbutyl glucosinolate
  • Major glucosinolate found within broccoli
  • Precursor of biologically active sulforaphane
    • Not present as such in Brassicaceae
    • Produced by enzymatic hydrolysis upon tissue disruption
      • Chewing of raw vegetables
      • Brings the endogenous enzyme beta-thioglucoside glucohydrolase (a myrosinase) into contact with the glucosinolate

In vitro and animal models

  • Broccoli sulforaphane can mitigate effects of inducers of inflammation and cell damage
    • Carcinogens, toxins and ROS
  • Inhibition of enzymes responsible for
    • Reactions related to oxidation,
    • Reduction and hydrolysis (i.e., cytochrome P450 enzymes),
  • Induction of antioxidant and detoxification enzymes
    • Quinone reductase,
    • Thioredoxin reductase 1,
    • Heme oxygenase 1
      • Phase II antioxidant enzymes
      • An important protective role in the maintenance of redox state in mammalian cells
        • By providing a balance between the level of ROS and endogenous thiol buffers
        • Protect cells from oxidative stress-induced damage
  • Critical role in maintaining the NAD+/NADH and NADP+/NADPH ratios
  • Dietary supplementation with the sulforaphane precursor glucoraphanin
    • Potent method for improving liver function and maintaining good liver condition
  • Glucoraphanin in the modulation of mitochondrial function
    • By control of FAD levels - redox cofactor of important reactions in energetic metabolism
  • FAD acts as cofactor of lysine-specific demethylase-1,
    • Modulates the expression of genes involved in mitochondrial metabolism and energy expenditure
  • FAD levels high:
    • Expression of genes associated with mitochondrial respiration is down-regulated
    • Export of citrate from the Krebs cycle is enhanced
    • Results in elevated concentrations of fatty acids, lipids and steroids
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm


Glucosinolates

  • Sulphur-containing plant secondary metabolites
  • Cruciferous plants
  • Containing a thioketal-linked glucose molecule and are hydrolysed by specific enzymes (i.e., myrosinases)
    • To produce biologically active sulfureted aglycones, the isothiocyanates
  • Glucosinolates and their respective enzymatic hydrolysis
    • Scavange harmful radicals
    • Modulate enzymes involved in detoxification processes
      • Preventing oxidative damage.
  • Www.wjgnet.com/1007-9327/full/v23/i23/4146.htm==
  • These molecules can suppress the activation of hepatic macrophages
  • Contribute to decrease liver damage
  • Protect against the development of liver tumorigenesis
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm


Glutathione

  • Liver’s most powerful detoxifier
  • Strongly anti-inflammatory

N-acetyl cysteine

  • Precursor of glutathione

Eating sulfur rich foods

  • Also helps with glutathione;
  • Eggs, cabbage, broccoli and garlic,...

Glykosurika - sodium glucose co-transporter 2 (SGLT2) inhibitors

  • Increasing the urinary glucose
  • Calorie excretion leading to ameliorated plasma glucose levels
  • Lower bodyweight

Several animal studies and human clinical trial

  • Possible beneficial impact of SGLT2 inhibitors on NAFLD and its progression to NASH
  • SGLT2 inhibitors seem to be an appealing therapeutic opportunity for NAFLD management
  • pubmed.ncbi.nlm.nih.gov/33439540/

Gossypol

  • Ameliorates liver fibrosis in diabetic rats induced by high-fat diet and streptozocin.

Green Tea (Camellia sinensis)

  • Chen N, Bezzina R, Hinch E, et al. Green tea, black tea, and epigallocatechin modify body composition, improve glucose tolerance, and differentially alter metabolic gene expression in rats fed a high-fat diet. Nutrition Research, 2009. DOI: 10.1016/j.nutres.2009.03.011

Další potenciálně vhodné látky a benefity při jaterní statoze v kapitole hepatoprotektiva




Hesperidin and diosmin

  • Used for the treatment CVI.

Study, male Wistar albino rats were fed a lipid-rich diet

  • With or without 450 mg diosmin-50 mg hesperidin-containing drug (60 mg kg(-1) body weight/day, per os) for 9 days
  • Free SH-group concentration (SHC), hydrogen-donating ability (HDA), and natural scavenger capacity
    • Were decreased
  • Hepatic malonaldehyde content and dien conjugate (DC) content in rats with fatty liver
    • Were increased compared to the control
  • After treatment in fatty liver, these parameters (except DC)
    • Significantly improved and approached the control value
  • Results indicate that diosmin-hesperidin-containing drug may be a useful agent in improving the antioxidant defensive system in alimentary-induced fatty liver disease.
  • https://pubmed.ncbi.nlm.nih.gov/17365719/
  • www.tandfonline.com/doi/abs/10.1080/14786410500518545

Hesperidin

  • Improves hepatic steatosis, hepatic enzymes, and metabolic and inflammatory parameters
    • In patients with nonalcoholic fatty liver disease

A randomized, placebo-controlled, double-blind clinical trial

  • 50 NAFLD patients were supplemented with either
    • 1-g hesperidin capsule
    • Placebo capsule for 12 weeks
    • Advised to follow healthy lifestyle habits including dietary and physical activity
  • Hesperidin supplementation, compared with placebo, was associated with a significant
    • Reduction in alanine aminotransferase (p = .005),
    • Gamma-glutamyltransferase (p = .004),
    • Total cholesterol (p = .016),
    • Triglyceride (p = .049),
    • Hepatic steatosis (p = .041),
    • High-sensitivity C-reactive protein (p = .029),
    • Tumor necrosis factor-alpha,
    • Nuclear factor-kappaB
  • Results indicate that hesperidin supplementation accompanied with lifestyle modification
    • Is superior to lifestyle modification alone in management of NAFLD
  • Further studies with higher dose of hesperidin are required to find the optimal dose.
Makan Cheraghpour 1, Hossein Imani 2, Shahrzad Ommi 3, Seyed Moayed Alavian 4, Elahe Karimi-Shahrbabak 5, Mehdi Hedayati 6, Zahra Yari 7, Azita Hekmatdoost 7


Hypericin


IMM-124e

  • IgG-enhanced bovine-derived colostrum
  • With favourable results in preliminary clinical studies including
    • Improved glycaemic control,
    • Insulin resistance and lipid profile
  • Studies are ongoing
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302

Indole propionic acid + other indole-like molecules

  • Maintain the integrity of intestinal epithelial barrier
  • Control inflammation
  • Can directly act on hepatocytes and liver immune cells
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Infliximab and prednisone

Group of 20 patients with alcoholic steatohepatitis

  • Only the combined use of infliximab and prednisone
    • Resulted in some clinical improvement after 28 days of treatment (Spahr et al. 2002)

Animal model fed on a high-fat diet -infliximab


Inhibition of gut-derived serotonin synthesis

Gut-specific Tph1 knockout mice

Liver-specific Htr2a knockout mice

Selective HTR2A antagonist treatment



Inhibition of tumour necrosis factor (TNF)-alpha

Monoclonal antibody infliximab

  • Ten days of treatment with infliximab
    • Significantly reduced the expression of the proinflammatory markers, TNF-alpha , IL-6, IL-1beta , and SOCS-3
      • In the liver of rats fed a high-fat diet
    • Accompanied by reduced fat deposition and fibrosis
    • By improved insulin signal transduction through insulin receptor (IR)/IR substrate/Akt/FOXO1 and JAK2/STAT3 pathways
  • Short-term inhibition of TNF-alpha with infliximab
    • Reduces inflammation and steatosis/fibrosis
      • While improving insulin signal transduction in an animal model
  • joe.bioscientifica.com/view/journals/joe/194/3/1940539.xml

Insulin sensitizer therapy


Kardio-metabolic/hepatic medication

  • Strong evidence of benefit for HFrEF and NAFLD

Angiotensin-converting enzyme inhibitors (ACEIs)

Angiotensin receptor blockers (ARBs)

  • Reduce fibrosis and fat deposition in the liver

Mineralocorticoids receptor antagonist (MRA)

Spironolactone

  • Clear effect on the combination of this diuretic with vitamin E

Sodium-glucose cotransporter 2 inhibitors (SGLT-2i)

  • Reduce liver stiffness and improve steatosis

Currently no data on beneficial effects on NAFLD


Carnitine

  • Malaguarnera M, Gargante MP, Russo C, et al. L-Carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis—a randomized and controlled clinical trial. American Journal of Gastroenterology, 2010. DOI: 10.1038/ajg.2009.741

Fish roe, or caviar

  • Excellent source of choline
  • 3 ounces (85 grams) of mixed-species caviar contains 285 mg, or 52% of the RDI
  • Caviar is also packed with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
    • Both of which have anti-inflammatory properties
  • www.healthline.com/nutrition/foods-with-choline#3.-Caviar

Ketodieta

Ten overweight/obese subjects received stable isotope infusions of

  • [D7]glucose,
  • [13C4]ß-hydroxybutyrate
  • [3-13C]lactate
  • Before and after a 6-d KD
  • IHTG was determined by proton magnetic resonance spectroscopy (1H-MRS)
  • KD diet decreased
    • IHTG by 31%
    • 3% decrease in body weight
    • Decreased hepatic insulin resistance (-58%)
    • Increase in NEFA concentrations (+35%)
      • Attributed to increased net hydrolysis of IHTG
      • Partitioning of the resulting fatty acids toward ketogenesis (+232%)
        • Due to reductions in serum insulin concentrations (-53%)
        • Hepatic citrate synthase flux (-38%)
  • Former was attributed to decreased hepatic insulin resistance
  • Latter to increased hepatic mitochondrial redox state (+167%)
    • Decreased plasma leptin (-45%) and triiodothyronine (-21%) concentrations
  • Data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD:
    • That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.
  • pubmed.ncbi.nlm.nih.gov/32179679/

Ketogenic diet (KD)

  • Diet very low in carbohydrates (<30 g/die)
  • Induces "physiological ketosis"
  • Demonstrated to
  • Potential therapeutic role of KD in NAFLD
    • Interplay between mitochondria and the liver
    • Effects of ketosis on oxidative stress pathways
  • pubmed.ncbi.nlm.nih.gov/37237931/

Kill-off senescent cells

  • To decrease the build-up of unwanted fat in the liver
  • Restore liver function to normal.
  • As we age we accumulate cell damage
    • These older cells are storing excess fat due to their inefficient mitochondria.
  • To reverse this damage in mice by removing these older, worn-out cells, which opens the door to a potential cure

Dasatinib and quercetin (D+Q)

  • Known to specifically kill senescent cells.
  • Approache was successful in reducing the build-up of fat in the liver caused by a high fat diet or ageing in mice.
  • Senescent cells are the cause of many diseases and we now have a way to fight them off
Dr Diana Jurk from Newcastle University’s Institute for Ageing


Turmeric curcumin

  • High doses of the turmeric compound curcumin
    • May lessen the indicators of liver damage in those with NAFLD.
  • According to studies on turmeric supplementation
    • ALT and AST, may be reduced by the vibrant orange root.


L-selenocystine


Lactobacillus casei shirota

Phase 2 trial assessing for reduction in serum M30 antigen levels

  • And other indicators of hepatocellular injury and fibrosis in patients with elevated M30 antigen levels (cutoff: >200–800 U/L) at screening and hepatic steatosis on ultrasound or histologically confirmed NASH.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5906104/

Lactulose

  • Prebiotic promotes the growth of Bifidobacteria, Lactobacillus, and Gram-positive bacteria
  • Inhibits the endotoxemic Gram-negative bacteria

HFD-fed obese mice that were administered lactulose for 6 wk

  • Showed reduced inflammation and liver damage
  • Correlated to decreased circulating levels of lipopolysaccharides
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Fungal prebiotic chitin-glucan


Feeding of cuticles from Tenebrio molitor larvae

Obese Zucker rats

  • Modulates the gut microbiota
  • Attenuates hepatic steatosis


Licorice root

Randomized double-blind clinical trial in women with nonalcoholic fatty liver disease (NAFLD), placebo-controlled trial

  • 60 women with NAFLD
  • 1,000 mg/day powder of licorice root extract
  • Placebo for 12 weeks
  • All the patients were advised to follow a weight loss diet and healthy lifestyle
  • Compared to the placebo group, powder of licorice root made statistically significant improvement in:
    • Alanine aminotransferase (p < .001),
    • Insulin (p = .002), insulin resistance (p = .003),
    • Malondialdehyde (p < .001) serum levels
    • Ultrasonographic findings of liver steatosis (p < .001)
  • Licorice root supplementation in addition to gradual weight loss and lifestyle modification is superior to lifestyle modification alone for the treatment of NAFLD.
Pouya Rostamizadeh 1, Seyed Mohammad Kazem Hosseini Asl 2, Zohreh Ghaem Far 1, Pegah Ahmadijoo 1, Trias Mahmudiono 3, Dmitry Olegovich Bokov 4 5, Fahad Alsaikhan 6, Behrooz Jannat 7, Zohreh Mazloom 1; PMID: 35785498 DOI: 10.1002/ptr.7543


Licorice Root (Glycyrrhiza glabra):

  • van Rossum TG, Vulto AG, Hop WC, et al. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial. Journal of Gastroenterology and Hepatology, 1999. DOI: 10.1046/j.1440-1746.1999.01936.x

Randomized double-blind, placebo-controlled trial, 60 women with NAFLD

  • 1,000 mg/day powder of licorice root extract
  • Or placebo for 12 weeks
  • Advised to follow a weight loss diet and healthy lifestyle
  • 12-weeks period of supplementation, women who received powder of licorice root statistically significant improvement in
    • Alanine aminotransferase (p < .001),
    • Insulin (p = .002),
    • Insulin resistance (p = .003),
    • Malondialdehyde (p < .001) serum levels,
    • Ultrasonographic findings of liver steatosis (p < .001),
  • Compared to the placebo group
  • Licorice root supplementation in addition to gradual weight loss and lifestyle modification
    • Is superior to lifestyle modification alone for the treatment of NAFLD.
  • pubmed.ncbi.nlm.nih.gov/35785498/

Lipid-lowering drugs

  • Decrease VLDL
    • Reducing lipid mobilization [1]

Liraglutide

  • Ameliorates hepatic steatosis via retinoic acid receptor-related orphan receptor ?-mediated autophagy pathway
  • Analog of human glucagon-like peptide-1 (GLP-1)
  • Improve hepatic steatosis in clinical practice
  • Retinoic acid receptor-related orphan receptor alpha (RORalpha)
    • Involved in hepatic lipid accumulation
  • Liraglutide treatment significantly alleviated HFD-induced liver steatosis,
    • Marked by reduced liver weight and triglyceride accumulation
    • Improved glucose tolerance and serum levels of lipid profiles and aminotransferase.
  • Liraglutide also ameliorated lipid deposits in a steatotic hepatocyte model in vitro.
  • Liraglutide treatment reversed the HFD-induced downregulation of Rora expression and autophagic activity in mouse liver tissues.

Ablation of Roralpha in hepatocytes

  • Diminished liraglutide-induced autophagosome formation
    • Fusion of autophagosomes and lysosomes,
      • Resulting in weakened autophagic flux activation
  • RORalpha is essential for the beneficial impact of liraglutide on lipid deposition in hepatocytes
    • And regulates autophagic activity in the underlying mechanism.
  • pubmed.ncbi.nlm.nih.gov/37310057/

Lisinopril and hydrochlorothiazide


Liver and kidneys

  • Are some of the best sources of choline.
  • 3 ounces (85 grams) of cooked beef liver
    • Provides 359 mg
    • 65% of the RDI for this nutrient
  • Organ meat is rich in a number of other vitamins and minerals, including
  • Small amount of organ meat to your diet
    • Can help cover nutritional gaps of important nutrients like choline
  • www.healthline.com/nutrition/foods-with-choline#2.-Organ-meat

Losartan

  • Angiotensin receptor blocker (ARB)
  • Disrupts the renin–angiotensin system
    • Thought to be upregulated in the development of chronic liver disease
  • Angiotensin-II (AT-II) induces proliferation of hepatic stellate cells
  • Upregulates the expression of TGF-beta, inducing liver fibrogenesis
  • AT-II receptor activation
    • Induces TFG-beta1
    • Upregulates the production of matrix proteins
    • Prevents matrix degradation
    • Stimulates expression of integrins
      • Collectively facilitate matrix production

Methioninecholine-deficient rat model for NASH

  • ARB diminished increases in AST and activation of hepatic stellate cells
  • Reduced the extent of liver fibrosis by 70% compared to placebo
  • Expression of type 1 collagen alpha 1 mRNA was significantly reduced
    • Corresponding to a 51% reduction in TGF-beta1 m RNA expression

8 patients with NASH and hypertension

  • Treated with losartan 50 mg daily for 48 weeks
  • Systemic blood pressure was significantly decreased in all patients
  • AST, ALT, GGT, TGF-beta1, and serum ferritin concentration were all significantly reduced
  • Histological improvement of necroinflammation occurred in five patients
  • Reduction in hepatic fibrosis in four
  • Disappearance of iron deposition in two
  • No adverse effects were observed in the study

The phase 3 Anti-Fibrotic Effects of Losartan In Nash Evaluation (FELINE) trial


Losartan

  • 100 mg in children
    • Reduced alkaline phosphatase, but not ALT at 24 wk
  • Losartan 50 mg in children
    • Reduced ALT more frequently than those patients with placebo
  • Losartan
    • Significantly decreased steatosis degree and visceral adipose tissue
    • Addition of simvastatin further decreased those parameters
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Lycopene

  • Carotenoid that lacks provitamin A activity
  • Responsible for the red to pink colours seen in
    • Tomatoes,
    • Red grapefruit,
    • Watermelon
    • Apricots.
  • Lycopene may have chemopreventive properties against certain types of cancers,
    • Including NASH-promoted hepatocarcinogenesis,
    • Mainly as a consequence of oxidative stress decrease
  • Lycopene also reduces the development of hepatic steatosis induced by an HF diet
  • Reduced plasma lycopene levels in subjects affected by NASH
  • Possible link between low lycopene levels and the development of liver diseases
  • Effect of lycopene on mitochondrial function has been proposed in cardiomyocytes
  • Important factor associated with mitochondrial dysfunction is activation of the mitochondrial permeability transition pore (mPTP)
    • Activation of mPTP leads to functional breakdown, and subsequently morphological disintegration of the mitochondria progresses to cell death
  • Lycopene was shown to suppress the activation of mPTP
    • By reducing intracellular ROS levels
    • Inhibiting oxidative damage
    • Impairment of mitochondrial membrane potential and decrease in ATP levels were alleviated
  • Ability of lycopene to enhance the mitochondrial activity in HepG2 cells that were exposed to aflatoxin B1
  • Improve the mitochondrial function in nervous system of rats that were exposed to 3-nitropropionic acid
  • Antioxidative potential of lycopene
    • Preserve the activity of endogenous free radical scavengers and of respiratory chain complexes directly
      • Thus preventing ROS production and secondary oxidative damage.
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm

Mediterranean Diet:

  • Ryan MC, Itsiopoulos C, Thodis T, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. Journal of Hepatology, 2013. DOI: 10.1016/j.jhep.2012.09.030


Melatonin

  • Alleviates cadmium-induced nonalcoholic fatty liver disease
    • In ducks
    • By alleviating autophagic flow arrest via PPAR-alpha + reducing oxidative stress
  • pubmed.ncbi.nlm.nih.gov/37343350/
  • Mantovani G, Maccio A, Madeddu C, et al. Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status. International Journal of Cancer, 2002. DOI: 10.1002/ijc.10216


Metformin Combined with PGG

Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase in mice

  • Induce the expression of glycine N-methyltransferase (GNMT)
    • Important enzyme regulating S-adenosylmethionine metabolism
    • Expression is downregulated in patients with NAFLD

1,2,3,4,6-pentagalloyl glucose (PGG)

  • Is a GNMT inducer

Metformin

Combination of PGG and metformin

  • Nearly completely reversed
    • Weight gain
    • Elevation of serum aminotransferases
    • Hepatic steatosis and steatohepatitis
  • Downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored.
  • PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity
  • Increased expression of
    • Glutathione S-transferase mu 4 (GSTM4),
    • Heat shock protein 72 (HSP72),
    • Pyruvate carboxylase (PYC)
    • 40S ribosomal protein S28 (RS28)
  • In the metformin plus PGG treatment group
  • Therapeutic potential for patients with NAFLD.
  • www.mdpi.com/1422-0067/23/17/10072

Methionine

  • Methionine has to be converted to S-adenosylmethionine (SAM)
    • In order to be utilized for functions such as phosphatidylcholine synthesis
  • SAM also provides a source of cysteine
    • Via the trans-sulphuration pathway
      • For reduced glutathione (GSH) production
        • A major hepatoprotective agent against liver injury, including lipid peroxidation.

SAM administration

  • In repleting GSH levels has been demonstrated in the baboon (Lieber et al., 1990)
  • In clinical studies (see Fig. 1) (Vendemiale et al., 1989).

Methionine may be deficient in alcohol-treated rats


Milk thistle (Silybum marianum)

  • Contains a compound called silymarin, which has antioxidant and anti-inflammatory properties. Studies have shown that silymarin may help protect liver cells from damage, reduce inflammation, and promote liver regeneration.
  • fattyliver.ca/blog/f/fatty-liver-disease-can-be-reversed
  • Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytotherapy Research, 2010. DOI: 10.1002/ptr.3207

Silybum marianum oil


N-acetylcysteine

  • Prekurzor glutathionu

Necrosulfonamide

  • Controls insulin sensitivity and TG depositions in the liver
  • Enhanced fat depletion in PHH,
  • Increased efficiency of other defatting agents
  • Enhance exogenous fatty acid oxidation
  • Promote lipogenesis
  • Induction of TG secretion and macro-autophagy
  • Inhibitor of the mixed lineage kinase domain like pseudokinase
    • Reported to regulate insulin sensitivity and TG deposition in the liver
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext

Niacin

  • Clinically for over half a century for dyslipidemia

New evidence

  • niacin may be useful in the treatment of nonalcoholic fatty liver disease (NAFLD)
    • Sequential complications including nonalcoholic steatohepatitis and fibrosis

Animals

  • Niacin inhibits and reverses hepatic steatosis and inflammation in animals and liver cell cultures
  • Prevents liver fibrosis in animals
  • Decreases collagen in cultured human stellate cells
  • Inhibition of diacylglycerol acyltransferase 2

Uncontrolled clinical trial in 39 hypertriglyceridemic patients with steatosis

  • Reduction of liver fat by 47%
  • Reductions in liver enzymes and C-reactive protein
    • From the baseline when treated with niacin extended-release for 6 months

Niacin beneficially affects NAFLD at 3 major stages

  • Directly and, by affecting steatosis,
  • Indirectly decreases the cascade effect on inflammation and fibrosis
  • Offers the advantage potentially of combination with other drugs in development
  • Benefit frequently associated atherogenic dyslipidemia
  • pubmed.ncbi.nlm.nih.gov/31706905/
  • Vitamin derived from tryptophan metabolism
  • Known for its effect on dyslipidemia
  • niacin reduces hepatic fat accumulation and steatosis, inflammation, and fibrosis
    • By inhibiting diacylglycerol acyltransferase 2
    • Blocking the activation of hepatic stellate cells
    • Decreasing the activity of matrix metalloproteinases 2 and 9
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Obeticholic acid (OCA)

  • On NASH and its metabolic features have been reported.
  • OCA is a selective farnesoid X receptor (FXR) agonist
  • With anticholestatic and hepato-protective properties

Study of patients with T2D and NAFLD

The OCA treatment group showed

  • Increases in triglycerides and LDL cholesterol
  • Modest decrease in HDL
    • Necessity for long-term monitoring
  • 23% of the OCA group reported pruritus.
  • Improvement in the liver histology provides encouraging results
    • Long-term effects are unknown
  • Improvement of liver enzymes regressed upon discontinuation of OCA
    • To obtain the therapeutic benefit of OCA, long-term administration is necessary
  • Further evaluation is imperative to determine long-term efficacy, safety, and tolerability.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5906104/
  • Obeticholic acid (OCA) for treating primary biliary cirrhosis and nonalcoholic fatty liver disease
  • By inhibiting bile acid synthesis
  • Brown adipogenesis differentiation in vitro and db/db mouse model treated with OCA
  • OCA increased whole-body energy metabolism and glucose homeostasis
    • By enhancing BAT activity in vivo
    • Decreased body weight gain in db/db mice
  • Spontaneous hepatic steatosis in db/db mice was ameliorated following OCA treatment
  • www.spandidos-publications.com/10.3892/etm.2021.10423

Healthy fats


Oleuropein


Oligofructose

  • Mixture of nondigestible fermentable dietary fiber
  • Reduced liver oxidative stress and inflammation
    • By improving intestinal permeability and tight junction integrity.
  • Prebiotics stimulated the growth of Bifidobacteria
    • Normalized plasma endotoxin levels
    • Improved glucose tolerance
      • Subsequently resulted in weight loss in obese individuals
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Lactulose

  • Prebiotic promotes the growth of Bifidobacteria, Lactobacillus, and Gram-positive bacteria
  • Inhibits the endotoxemic Gram-negative bacteria

HFD-fed obese mice that were administered lactulose for 6 wk

  • Showed reduced inflammation and liver damage
  • Correlated to decreased circulating levels of lipopolysaccharides
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Fungal prebiotic chitin-glucan


Synbiotics

  • Probiotics and prebiotics.

Bifidobacterium and fructo-oligosaccharides (FOS) - for 6 months

  • Showed significantly lower serum ALT and AST levels compared to the placebo group
  • Potential advantage of using synbiotics against liver diseases

Synbiotic supplementation with seven probiotic strains - and FOS for 28 wk

  • Lactobacillus casei, L. bulgaricus, Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium breve, B. longum, and S. thermophilus
  • Along with healthy lifestyle modifications
  • Supplementaton was more beneficial (in terms of reduced inflammation and BMI) to NAFLD patients
    • Compared to lifestyle changes alone

Co-administering B. longum and FOS for 24 wk + healthy lifestyle

  • Significantly decreased NASH activity index and hepatic fat accumulation

Long-term synbiotic treatment

  • Significantly decreased serum lipid levels in obese children.

A meta-analysis of 15 randomized controlled trials - 782 NAFLD patients

Fecal transplantation

  • Transferring functional microbiomes from the feces of healthy individuals
    • To the gastrointestinal tract of patients with intestinal dysbiosis.

Chinese medical and herbal practitioners for treating severe diarrhea and food poisoning

  • Effective therapeutic option for recurrent Clostridium difficile infection
    • As well as liver and metabolic diseases associated with intestinal microbiota dysbiosis

Clinical studies conducted so far on microbiota-targeting strategies, including FMT, in NAFLD patients

  • Several studies have demonstrated the therapeutic effects of FMT on
    • Type 2 diabetes
    • Ulcerative colitis patients
    • Associated with restored healthy microbiota, normalized blood lipid levels, and improved insulin resistance.
  • FMT is a potential therapeutic option for NAFLD and NASH as well

Le Roy et al. transplanted the feces from HFD responder and non-responder mice into germ-free recipients

  • Mice that received microbiota from the responder group developed steatosis
    • Showed a high abundance of Barnesiella and Roseburia in the intestine
  • Microbiota from the non-responder mice
    • Markedly increased the abundance of Allobaculum in the recipients
  • 8-wk FMT intervention significantly restored the disordered gut microbiota in HFD-induced NASH mouse models
    • By increasing the abundance of beneficial bacteria such as Christensen and Lactobacillus
  • Alleviated endotoxemia, liver steatosis, necrosis, and intra-hepatic inflammation
    • Compared to the untreated controls

Metabolic syndrome patients transplanted with the gut microbes of healthy individuals

  • Showed increased butyrate production
  • Improved insulin sensitivity
  • Higher abundance of beneficial bacteria in the lower gut.

Short chain fatty acids (SCFA)

  • Ameliorative effects in cancer, metabolic diseases, and other diseases
  • Produced during the fermentation of dietary fiber in the gut
  • Fuel for gut epithelial cells
  • Regulates multiple metabolic pathways in the intestine
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Bile acid (BA)

  • cholesterol derivative that is synthesized and conjugated in the liver
  • Central role in digestion by emulsifying dietary fats
  • Promoting the absorption of lipids and vitamins in the small intestine (mainly the ileum)
  • BA is a critical signaling molecule - connects the intestine and liver

BA receptor (BAR) - known as FXR

  • Highly expressed in the liver and intestine
  • Regulates the synthesis of bile acids through a feedback mechanism
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

TGR5

  • Another major BAR in the liver
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Amino acid catabolites

  • Regulatory role in NAFLD
    • By influencing intestinal epithelial barrier
    • Therapeutic effects on liver function
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Indole propionic acid + other indole-like molecules

  • Maintain the integrity of intestinal epithelial barrier
  • Control inflammation
  • Can directly act on hepatocytes and liver immune cells
Chen HT, Huang HL, Li YQ, Xu HM, Zhou YJ. Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view. World J Gastroenterol 2020; 26(16): 1901-1911 [PMID: 32390701 DOI: 10.3748/wjg.v26.i16.1901]

Olive Oil:

  • Ryan M, McInerney D, Owens D, Collins P, Johnson A, Tomkin GH. Diabetes and the Mediterranean diet: a beneficial effect of oleic acid on insulin sensitivity, adipocyte glucose transport, and endothelium-dependent vasoreactivity. Diabetes, 2000. DOI: 10.2337/diabetes.49.5.775

Oltipraz

  • PharmaKing (Korea)
  • An external file that holds a picture, illustration, etc.

Phase 3 LXR-? inhibitor Patients with NAFLD


DHA + HT (hydroxythyrosol from olive oil)



Omega 3-rich Camelina sativa oil

  • Benefits of omega-3 fatty acids have been reported in the management of non-alcoholic fatty liver disease (NAFLD) complications.

Patients with NAFLD: A randomised placebo-controlled clinical trial

  • 46 patients with NAFLD
    • Intervention (20 g/d CSO)
    • Placebo (20 g/d sunflower oil) group
    • Calorie-restricted diet for 12 weeks

Results for CSO supplementation significant differences between the two groups in

  • Insulin concentration, quantitative insulin sensitivity check index, LPS, TAC, SOD, glutathione peroxidase activity, MDA and 8-iso-PGF2? changed significantly only in CSO group (P < .05).
  • CSO may improve glycemia, inflammation, metabolic endotoxemia, and oxidative stress status in patients with NAFLD.
  • PMID: 34423525, DOI: 10.1111/ijcp.14744, © 2021 John Wiley & Sons Ltd.
  • Desaturases (FADS1 and FADS2)
  • Elongases (genes of the ELOVL family)
  • Acting on LA (o6) and ALA (o3) lead to the production of:
    • N-6 long-chain polyunsaturated fatty acids (LCPUFA)
      • Arachidonic acid (AA; n-6; 20:4; among others; synthetized from LA)
      • N-3 LCPUFAs eicosapentaenoic acid (EPA; n-3; 20:5)
      • Docosahexaenoic acid (DHA; n-3; 22:6)

Arachidonic acid

  • ALA adequate intake in children
    • 0.7 g/day in 1–3 years old (both male and female),
    • 0.9 g/day in 4–8 years old (both male and female),
    • 1 g/day (9–13 years old; female)
    • 1.2 g/day (9–13 years old; male).
    • 14 years - adulthood 1.1 g/day (female) and 1.6 g/day (male)
    • 0.25–2 g/day in adults
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/

Nobili et al. 2011, 2013, Italy 60, pod 18 years

  • DHA 500 mg/day, or DHA 250 mg/day, or placebo
  • For 24 months
  • Change in liver fat (detected by ultrasonography)
  • TG, ALT, BMI, HOMA-IR The severity of liver steatosis decreased in both treated groups vs. placebo
  • TG were lower in both the treated groups.
  • ALT was lower in the treatment groups from month 12 onwards.
  • HOMA was lower in the DHA 250 mg group vs. placebo at 6 and 12 months.

Boyraz et al. 2015, Turkey 108 obese adolescents, 9–17 years

  • 1000 mg/day omega-3 plus diet
  • Lifestyle intervention
    • Exercise 3x per week for 1 h
    • Promotion of self-initiated physical activities
  • Placebo plus diet plus lifestyle intervention for 12 months
  • US, ALT, AST, BMI, HDL-C, TG, TC, FI, FG, IS, HOMA-IR, SBP Improvement of steatosis, ALT and AST Increase HDL-C, improvement of TG, FI and HOMA-IR, Improvement in BMI in both groups.
  • Improvement of SBP in the intervention group.

Janczyk et al. 2015, Poland 76

  • 450–1300 mg/day 3:2 DHA:EPA + individually prescribed diet
  • Versus omega 6 sunflower oil for 6 months
  • Lower ALT levels in both groups
  • Lower AST and GGT levels in the intervention group.
  • No changes in ALT, steatosis, FSG, FI, HOMA-IR, BMI z score or WC z score in both groups.

Omega 3 a olivýv olej (hydroxythyrosol)

animal study of natural products in the preclinical high-fat diet (HFD) protocol

  • 60% of fat for 12 weeks
  • Eicosapentaenoic acid (C20:5n-3, EPA) and docosahexaenoic acid (C22:5n-3, DHA), DHA and extra virgin olive oil (EVOO)
  • EPA plus hydroxytyrosol (HT) attained 66% to 83% diminution in HFD-induced steatosis
    • With the concomitant inhibition of the proinflammatory state associated with steatosis
  • These supplementations modify antioxidant, antisteatotic, and anti-inflammatory responses

DHA and HT co-administration, prevent NAFLD



Omega 3

  • Imbalance in the n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA in the Western diet
    • Increase the risk of nonalcoholic fatty liver disease (NAFLD).
  • High fat and fructose (HFHF) diet induced nonalcoholic steatohepatitis (NASH)

Male Sprague-Dawley rats 4 groups for 24 weeks

Control diet

HFHF diet (n-6:n-3 ratio of 200)

  • Resulted in hepatic steatosis, induced glucose intolerance,
  • Insulin resistance and oxidative stress accompanied by increase in markers of inflammation,
  • Elevation of plasma lipids and aminotransferase levels.
  • Histopathological examination of liver further confirmed the establishment of NASH.

HFHF diet with ALA (n-6:n-3 ratio of 2)

  • Prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity.

HFHF diet with LC n-3 PUFA (n-6:n-3 ratio of 5)

  • Prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity.
  • N-3 PUFA supplementation attenuated:
    • Hepatic oxidative stress by restoring antioxidant status,
    • Inflammation
  • Preserved hepatic architecture.

Omega-3 fatty acids



Omega3

Omega-3 LCPUFAs EPA/DHA may contribute to prevent/manage NAFLD through:

  • Induction of fatty acid oxidation
  • Reduction of de novo lipogenesis
    • Endogenous ligands of peroxisome proliferator-activated receptor-
      • Also activated by fibrates
  • Inhibition of the transcriptional regulators Carbohydrate Response-Element Binding protein (ChREBP)
  • Inhibition of Sterol Response Element Binding Protein 1c (SREBP1c)
  • Reduce inflammation
    • Precursors of mildly inflammatory or anti-inflammatory eicosanoids
    • Inhibitory effect on the production of AA-derived inflammatory eicosanoids
  • Modulation of microbiota
    • Reduction of endotoxemia

Low consumption of n-3 LCPUFAs and/or high n-6/n-3 ratios are risk factors for NAFLD development

In children, a cross-sectional study

  • Most children with NAFLD have insufficient intake of n-3 LCPUFAs (pod 200 mg/day)

Studies tested the beneficial effects of n-3 LCPUFAs administration on NAFLD

  • In adults and children/adolescents

A randomized controlled trial

  • 250 or 500 mg of DHA versus placebo
  • In 60 children with NAFLD
  • For two years
  • Indicated that DHA administration
    • Was effective in reducing fatty liver steatosis,
    • Possibly exerting anti-inflammatory actions
      • Via the G protein-coupled receptor GPR120

Using 1 g/day of n-3 LCPUFAs during a year

  • Reduction in hepatic steatosis
  • Improvement of plasma liver enzymes

Pacifico et al. using (250 mg oil/day, 39% DHA) vs. placebo

  • With decreased liver and visceral fat,
  • Improvements in plasma triglycerides and insulin sensitivity
  • Without changes in BMI and liver enzymes.

Randomized intervention using 450–1300 mg/day of EPA + DHA

  • For six months
  • In children with NAFLD
  • Did not reduce the ALT enzyme levels
  • Reduction in the AST level was achieved

A meta-analysis of randomized controlled trials in children

  • Administration of n-3 LCPUFA might reduce liver steatosis and liver function markers
    • Representing a possible nutritional approach to treat NAFLD in children

Spahis et al. - children with NAFLD with different degrees of severity

  • In response to n-3 LCPUFA supplementation (2 g/day for 1 year)
  • Important reductions of the hepatic steatosis, fatty liver index, hepatic enzyme activities (ALT and ALT/AST ratio), lipid profile, oxidative markers and carotid intima media thickness,
  • While enhancing circulating adiponectin in the n-3 LCPUFA group
    • Compared to the placebo

Another randomized trial: DHA + choline + vitamin E

  • May reduce steatosis, glycemia and liver enzyme activities in children with NASH

Meta-analyses of studies in adults and children

  • Reaffirm the positive effects of n-3 LCPUFAs on NAFLD
  • Proposed long-term studies focusing on NASH

Review article concluded



Optifast

  • Optifast-based diet for at least 4 weeks
  • No exercise regimen was required.
  • A short course of Optifast was well tolerated
    • Resulted in a consistent and rapid reduction of hepatic steatosis in all donors.
  • All post-Optifast biopsies showed pod 10% macrovesicular steatosis
    • After the completion of treatment.
  • Optifast-treated donors who proceeded to hepatectomy
    • Experienced similar postoperative outcomes as non-Optifast–treated donors.
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext


Ořechy


Oridonin

  • Significant liver-protective effects

Liver Cell cultures steatosis induced using free fatty acids (FFA)

  • After adding oridonin for 24 h
  • Model was further treated by autophagy inhibitor 3-methyladenine (3-MA)
  • Oridonin at a concentration higher than 10 mcmol/L caused cytotoxicity to the cells
  • 10 µmol/L oridonin to the FFA-induced cell model effectively reduced lipid droplets and TG content in the cells
    • Up-regulated p21, Beclin-1 and LC3-II expressions,
    • Down-regulated those of p62 and LC3-I.
    • Increased the ratios of LC3-II/LC3-I and p-AMPK/AMPK,
    • Reduced that of p-AKT/AKT
  • Addition of 3-MA
    • Effect of oridonin on reducing steatosis was partially reversed, and the autophagy was inhibited
  • Oridonin can activate autophagy, thereby preventing simple steatosis of liver cells.
  • pubmed.ncbi.nlm.nih.gov/33823340/


Orlistat



Ovesné vločky

Na mysim modelu

  • Inhibicni vliv ovesnych vlocek obsahujicich beta glukany a inulinu na progresi steatozy.
  • Napriklad vlocky se skyrem nebo tvarohem...
  • Blahodarmy efekt na mikrobiom a dokonce na jatra...

Ovesný beta-glukan

  • Na osu střevo-játra a vývoj fibrózy na myším modelu steatotického jaterního onemocnění spojeného s metabolickou dysfunkcí (MASLD).
  • Beta-glukan významně snížil zánět a fibrózu v játrech, což bylo spojeno s příznivými posuny střevní mikroflóry, která chránila před bakteriální translokací a aktivací fibrozánětlivých drah.
  • Společně může být ovesný beta-glukan nákladově efektivním a dobře tolerovaným přístupem k prevenci progrese MASLD a měl by být posouzen v klinických studiích.
  • Suplementace ovesným beta-glukanem
    • Neovlivnila WSD-indukovaný nárůst tělesné hmotnosti nebo intoleranci glukózy a metabolický fenotyp zůstal do značné míry nedotčen.
  • Ovesný beta-glukan tlumil zánět související s MASLD,
    • Který byl spojen s významně sníženou infiltrací makrofágů odvozenou od monocytů a expresí fibrozánětlivých genů, stejně jako silně sníženým rozvojem fibrózy.
  • Mechanicky nebyl tento ochranný účinek zprostředkován změnami ve složení žlučových kyselin nebo signalizací,
    • Byl závislý na střevní mikrobiotě
    • Při léčbě širokospektrými antibiotiky se ztratil.
  • Konkrétně ovesný beta-glukan částečně zvrátil nepříznivé změny ve střevní mikroflórě,
    • Což mělo za následek expanzi ochranných taxonů, včetně Ruminococcus a Lactobacillus,
    • Následovanou sníženou translokací ligandů Toll-like receptorů.
  • Ovesný beta-glukan, nestravitelný polysacharid, prokázal slibné terapeutické účinky na hyperlipidémii spojenou s MASLD

Pegozafermin

  • Mimicked fibroblast growth factor 21 (FGF21)
    • A liver-secreted peptide hormone that is naturally produced in the body.
  • FGF21 controls energy use in the body and lipid metabolism in the liver.
  • Shown in previous studies to lower blood glucose and insulin levels, reducing body weight and liver fat.
  • Potential treatment not only improves fibrosis
  • Improves inflammation and liver injury along with significant improvements across multiple non-invasive biomarkers of NASH activity and scarring

24-week, randomized clinical trial

  • 222 participants with NASH assigned to either receive the drug or a placebo.
  • Who received the drug at a higher dose
    • Cca 27% showed an improvement in liver fibrosis
    • Relative to 7% of the patients who received the placebo
  • Most frequent reported side effect nausea.
  • Next steps for this research will be a larger, multi-center, international trial with a more diverse patient population and longer treatment period
    • If successfully shown to be both safe and effective in a larger Phase 3 trial
  • health.ucsd.edu/news/press-releases/2023-06-26-study-potential-new-treatment-identified-for-liver-disease/

Pentoxifylline (PTX)

  • Methylxanthine derivative
  • Inhibitory effect on phosphodiesterase as well as on TNFalpha
  • Subset of patients with alcoholic hepatitis
  • Improved survival reported in these patients is currently in serious question
  • 400 mg three times daily for a year
    • Significant histological improvement was found with PTX in patients with biopsy-proven NASH
    • In 38.5% (n = 26) of the treatment group compared to 13.8% (n = 29) with placebo (P = .036)
  • Fibrosis decreased in more patients in the PTX group (35%) than in the placebo group (15%)
    • Not statistically significant
  • Reduction in lipid peroxidation
  • Glutathione-replenishing ability
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302

Perhexiline maleate

  • Cationic amphiphile antianginal drug
  • Previously used extensively in Europe
  • Hepatic toxicity is similar to amiodarone
  • Histologically mimicking alcoholic steatohepatitis
  • Associated with phospholipidosis
  • Drug impairs hepatic liver metabolism similarly to amiodarone
    • Concentrating in the mitochondria,
    • Uncouples oxidative phosphorylation
    • Inhibits b-oxidation of fatty acid
  • Perhexiline maleate also decreases the exit of triglycerides from the liver
    • Resulting in significant microvesicular steatosis, necrosis, and inflammation
  • Perhexiline is catabolized by cytochrome P-450 2D6
  • 3-7% of Caucasians are slow metabolizers for perhexiline
    • At a greater risk for steatohepatitis and neuropathy, another side effect of the drug
  • Perhexiline half-life is long, 3 to 12 days,
    • Resulting in delayed hepatic clearance,
      • Particularly in slow metabolizers
  • no longer in the United States market although continue to be used in some countries like Australia and New Zealand.
  • www.science.org/doi/10.1126/scitranslmed.aay0284

Phenylmethimazole (C10)

  • To prevent lipopolysaccharide and palmitate-induced TLR4 signaling.
  • Because TLR4 is a key mediator in pro-inflammatory responses, it is a potential therapeutic target for NAFLD.
  • C10 inhibits HF diet-induced inflammation in both liver and mesenteric adipose tissue measured
    • By a decrease in mRNA levels of pro-inflammatory cytokines
  • C10 treatment improves glucose tolerance and hepatic steatosis
    • Despite the development of obesity due to HF diet feeding.
  • Administration of C10 after 16 weeks of HF diet feeding
    • Reversed glucose intolerance,
    • Hepatic inflammation,
    • Improved hepatic steatosis
  • C10 as a potential therapeutic for the treatment of NAFLD.
  • pubmed.ncbi.nlm.nih.gov/29666152/

Phosphatidylcholine

  • Buchman AL, Dubin M, Moukarzel A, et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology, 1995. DOI: 10.1002/hep.1840210416

Patients with non-alcoholic fatty liver disease and cardiometabolic comorbidities (MANPOWER study)

  • 24-week, observational, prospective study
  • 174 medical sites across 6 federal districts of Russia
  • 2843 adult patients with newly diagnosed NAFLD, who had a least one of four comorbidities, namely overweight/obesity, hypertension, type 2 diabetes mellitus and hypercholesterolaemia, and who received PPC as an adjunctive treatment to standard care

Results

  • Almost all study participants (2837/2843; 99.8%) were prescribed 1.8 g of PPC administered three times daily
    • Liver hyperechogenicity (84.0% of patients) and heterogeneous liver structure (62.9%)
  • At 24 weeks
    • A significant (p<0.05) improvement in
      • Liver echogenicity in 1932/2827 (68.3%) patients (95% CI 66.6% to 70.1%)
      • Liver structure was observed in 1207/2827 (42.7%) patients (95% CI 40.9% to 44.5%)
  • bmjopengastro.bmj.com/content/7/1/e000341

Pimavanserin derivative

  • Reduce liver weight and hepatic lipid accumulation in HFD-induced NAFLD mice
    • At 50 and 100 mg/kg.
  • Results prompted to develop a more efficacious 5HT2A receptor antagonist for treating NAFLD
    • Compounds which contain amino acid moiety showed limited BBB
  • www.sciencedirect.com/science/article/abs/pii/S0223523422004196


Pioglitazone



Plant-Based Diet


Polyphenols

  • Polyphenols are secondary metabolites of plants
  • Potential roles to combat oxidative stress and inflammatory processes
    • flavonoids and nonflavonoids, based on their chemical structure

Flavonoids

  • Able to control de novo lipogenesis
    • Inhibiting lipogenic proteins
      • ACC, SREBP-1, FAS and LXR?
    • Increasing lipolytic proteins
      • AMPK, PPAR? and CPT-1
  • Effective scavengers of ROS and RNS
    • Superoxide, hydrogen peroxide, hydroxyl radicals and peroxynitrite
      • Elevated in pathological states and metabolic disorders such as NAFLD

Resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin

  • Evidence of the positive effects on the reversion of fatty liver
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm

Prevent bacterial or LPS ‘translocation’ to the systemic circulation and liver


Probiotics (Lactobacillus and Bifidobacterium strains):

  • Ferolla SM, Couto CA, Costa-Silva L, et al. Beneficial effect of synbiotic supplementation on hepatic steatosis and anthropometric parameters, but not on gut permeability in a population with nonalcoholic steatohepatitis. Nutrients, 2016. DOI: 10.3390/nu8110671


Probiotics

  • Can reduce lipid deposition, endotoxemia, oxidative stress, and inflammation
    • By regulating the expression levels of TNF-?, NF-?B, and collagen
  • Streptococcus, Lactobacillus, and Bifidobacteria strains
    • Can regulate the mucosa-motivated immune system
    • Gastrointestinal inflammation
    • Promote the growth and survival of gut epithelial cells

murine fatty liver model

  • Significant therapeutic effects

Mice fed an HFD

  • Significantly slowed the progression of hepatic steatosis and fibrosis

Most studies on NAFLD rodent models

  • Aimed at preventing, rather than treating, diet-induced liver disease

Clinical trials on NAFLD patients

Lactobacillus, Streptococcus, and Bifidobacterium strains

  • Play an ameliorative role by restoring the levels of the liver enzymes AST and ALT
  • Intra-hepatic levels of AST and ALT increased significantly in NAFLD patients following 3 mo of treatment with
    • Lactobacillus bulgaricus (L. bulgaricus)
    • Streptococcus thermophilus (S. thermophiles)[39]

MIYAIRI 588, a probiotic Clostridium butyricum strain

  • Originally from Japan and used widely in Asia
  • Prevented fatty degeneration from progressing to liver cancer in a rat NAFLD model

VSL3 formulation

  • 8 probiotic bacterial strains
    • S. thermophiles, Bifidobacterium breve, Bifidobacterium longum (B. longum),
    • Bifidobacterium infantis, Lactobacillus casei, Lactobacillus plantarum,
    • Lactobacillus acidophilus, and L. bulgaricus
  • Resulted in greater therapeutic effects compared to any single strain

A randomized controlled trial conducted on overweight children with NAFLD

  • Significant improvement in the fatty liver condition and BMI following treatment with VSL3
  • Increase in total and active GLP-1
  • Decrease in the plasma levels of S-nitrosothiols, malondialdehyde, and 4-hydroxynonenal
    • Was the potential mechanisms underlying the therapeutic effects of VSL3
  • VSL3 can alleviate chronic liver diseases
    • By protecting the intestinal barrier
    • Reducing endotoxemia and oxidative/nitrosative stress

Yeast (e.g., Saccharomyces boulardii)

  • Encouraging effects, especially when combined with traditional bacterial probiotics
  • Further research is needed to optimize the efficacy, safety, and sustainability of probiotics for treating NAFLD.

Lactobacillus bulgaricus and Streptococcus thermophilus

Double-blinded trial in 2011


Protein-rich diet, exercise and benzafibrate

  • For 2–8 weeks
  • Can reduce the risk of liver injury in living-donor liver transplantation candidates with steatosis
  • This regimen significantly reduced liver steatosis,
    • Determined by liver biopsy
      • From about 30% before treatment to around 12% after treatment
  • Body weight and BMI
    • Were also significantly reduced.
  • Eleven possible donors were treated,
    • 7 proceeded to live donation
  • Graft function and outcomes post-transplantation
    • Were similar in the recipients of these grafts compared to living donor recipients who received a lean graft.
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext

Protein


Proteiny

  • An adult should consume a minimum of 0.8-1 gram protein per kg body weight on a daily basis.
  • Most of us, especially vegetarians, do not even meet half of their requirements.
  • So, include one protein-rich source in every major and minor meal of the day to ensure you meet your daily requirements.


Pyrvinium pamoate

  • Attenuates non-alcoholic steatohepatitis
PMID: 32240652 DOI: 10.1016/j.bcp.2020.113942
  • Pyrvinium pamoate (PP)
    • Anti-adipogenic compound

Rats to HFD for 16 weeks and a single dose of streptozotocin (STZ) 35 mg/kg at the fifth week

  • Tenth week, PP was given orally at a dose of 60 mcg/kg
    • Day after day for 6 weeks
  • HFD/STZ induced significant steatohepatitis and insulin resistance
    • Elevated transaminases activity, NAFLD activity score and HOMA-IR level.
    • Precipitated in initiation of liver fibrosis with +TGF-b1, alpha-smooth muscle actin (a-SMA), liver collagen content
  • PP protected against HFD-induced NASH and liver fibrosis
    • Via downregulating the expression of key factors in Hedgehog and Wnt/ beta-catenin signaling pathway
  • PP can attenuate the progression of NASH and its associated sequela of liver fibrosis.
  • pubmed.ncbi.nlm.nih.gov/32240652/

Pyrvinium pamoate

  • Attenuates non-alcoholic steatohepatitis: Insight on hedgehog /Gli and Wnt/ beta-catenin signaling crosstalk.

Quercetin, Epigallocatechin Gallate, Curcumin, and Resveratrol

  • From Dietary Sources to Human MicroRNA Modulation.
  • Cione E, La Torre C, Cannataro R, Caroleo MC, Plastina P, Gallelli L., Molecules. 2019 Dec 23;25(1):63. doi: 10.3390/molecules25010063.

Quercetin:

  • Ejaz A, Wu D, Kwan P, Meydani M. Curcumin inhibits adipogenesis in 3T3-L1 adipocytes and angiogenesis and obesity in C57/BL mice. The Journal of Nutrition, 2009. DOI: 10.3945/jn.108.100966

Quercetin

  • Flavonoid antioxidant in plant foods, including
    • Leafy greens,
    • Tomatoes,
    • Berries
    • Broccoli
  • Beneficial effects of quercetin include
    • Activation of mitochondrial biogenesis
      • Through PGC-1a - transcriptional coactivator of genes associated with oxidative phosphorylation and mtDNA replication

HepG2 cells

  • Increase in mitochondrial biogenesis is associated with cytochrome oxidase subunit IV (COXIV) overexpression
  • Increase in cytochrome c concentration
  • Result is an overall increase in mitochondrial capacity

Animal models

  • 50 mg/kg and 100 mg/kg doses of quercetin
  • Significantly affect the mitochondrial biogenesis
  • Mice treated with up to 3000 mg/kg quercetin
    • Did not show any toxic effects
  • Effect of oral administration of quercetin on liver mitochondria has not been tested
  • Several reports indicating that quercetin exhibits both antioxidant and pro-oxidant activity, in a concentration dependent manner
  • Further studies are needed to determine the therapeutic efficacy of oral quercetin administration.
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm

Quinoa

  • Ameliorates Hepatic Steatosis, Oxidative Stress, Inflammation and Regulates the Gut Microbiota in Nonalcoholic Fatty Liver Disease Rats.
Zhong L, Lyu W, Lin Z, Lu J, Geng Y, Song L, Zhang H. Foods. 2023 Apr 25;12(9):1780. doi: 10.3390/foods12091780.


RIP3 deficiency

  • Attenuated MCD diet-induced liver injury, steatosis, inflammation, fibrosis and oxidative stress.
  • Necroptosis is increased in the liver of NAFLD patients and in experimental models of NASH.
  • TNF-alpha triggers RIP3-dependent oxidative stress during hepatocyte necroptosis.
    • Targeting necroptosis appears to arrest or at least impair NAFLD progression.
  • pubmed.ncbi.nlm.nih.gov/26201023/

Rapamycin (mTOR)



Redukce hmotnosti

  • NAFLD is leading cause of donor rejection in living donor liver transplantation program at our centre
  • Rapid weight loss
    • Is not recommended due to fear of worsening of inflammation
  • Difficult to achieve in clinical practice in poorly motivated asymptomatic NAFLD patients.
  • Rapid weight loss
    • Is often only option for prospective liver donors (in absence of other donors in family) who want to donate their liver to their loved ones
      • As they can't wait too long as they are too sick or have hepatocellular carcinoma.

From July 2010 to January 2015 - dárci jater k transplantaci s jaterní steatozou

  • Young donors, no co-morbidities, emotionally motivated for weight loss on a short term basis
  • Of 15 prospective liver donors who had paired liver biopsies.
  • They were advised 1200 Kcal per day diet (including 50–60 g proteins)
    • And minimum of 60 min moderate activity in the form of brisk walk (200–400 Kcal) as exercise
    • They were free to do more exercise if they wanted to do.
  • 16 donors were advised aggressive life style modification after initial biopsy
  • 15 (10 males, age 27.5 ± 6.5 years, baseline body mass index 28.4 ± 2.1 Kg/M2) successfully reduced weight
  • 14 underwent donation after favorable second biopsy
  • Mean weight loss was 7 ± 4.3 kg (8.4 ± 4.6%).
  • Second liver biopsy was done at 28 ± 10 days
    • Decrease in steatosis in all but one including normalization of liver biopsy in 7 donors
  • 3 donors had mild inflammation on first biopsy
    • Had improvement in second biopsy
  • All the donors and their recipients had an uneventful post-operative course.

Conclusion: Steatosis can be reversed


Restrikce sacharidů

A review of four studies published recently in the Journal of Research in Medical Sciences

2004 study published in the journal Digestive Diseases and Sciences

  • People whose carbohydrate intake was greater than 54 % of their total calories
    • Were 6,5 x more likely to have liver inflammation
    • Compared to those for whom carbohydrates made up less than 35 % of their total calories
  • Those who ate a high-fat diet
    • Had lower rates of inflammation in the liver
      • Counter to the long-held belief that dietary fat causes people to develop more fat in the body and the liver.
  • Zjevně také bude záležet druhu, na podobě a kvalitě oněch tuků.
  • www.uclahealth.org/news/ask-the-doctors-how-can-i-reverse-fatty-liver

Resveratrol

  • Bujanda L. The effects of resveratrol on non-alcoholic fatty liver disease. Alimentary Pharmacology & Therapeutics, 2016. DOI: 10.1111/apt.13665

Randomized, double-blinded, controlled clinical trial, 50 NAFLD patients

  • 500-mg resveratrol capsule
  • Placebo capsule for 12 weeks
  • Both groups were advised to follow an energy-balanced diet + physical activity
  • Resveratrol supplementation was associated with a significant
    • Reduction in
      • Liver enzyme alanine aminotransferase,
      • Inflammatory cytokines,
      • Nuclear factor kappaB activity
      • Cytokeratin-18,
      • Hepatic steatosis grade
    • Compared with placebo supplementation (P < .05)
  • 500 mg resveratrol, along with lifestyle modification, is superior to lifestyle modification alone
    • At least partially due to the attenuation of inflammatory markers and hepatocellular apoptosis
  • Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease
  • pubmed.ncbi.nlm.nih.gov/25311610/
  • Resveratrol (trans-3,4’,5-trihydroxystilbene)
  • Stilbene naturally found in various food stuffs
    • Grapes,
    • Berries,
    • Red wine
    • Nuts
  • Control energetic metabolism in obese mice,
    • Improving the glucose homeostasis,
    • Increasing the fatty acid oxidation
    • Inducing the expression of genes associated with the regulation of mitochondrial biogenesis
  • High resveratrol doses (10-100 µmol/L) on mitochondrial metabolism
    • Evaluated in different models
    • Able to increase the number of mitochondria in the tissues
    • Occurs via a sirtuin-dependent mechanism.
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm








Rhamnetin


Rosa mosqueta (RM) oil

  • Rich in alpha-linolenic acid (ALA)
    • Precursor of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)
  • High antioxidant activity
    • Tocopherols
  • RM oil administration prevents hepatic steatosis.

High-fat diet (HFD) fed mice model C57BL/6J mice

  • Control diet or a HFD
  • With and without RM oil supplementation for 12 weeks

Results


Dietary Rosa mosqueta (Rosa rubiginosa) oil


S-Adenosylmethionine (SAMe):

  • Mato JM, Lu SC. Role of S-adenosyl-L-methionine in liver health and injury. Hepatology, 2007. DOI: 10.1002/hep.21689


SGLT-2i

  • Suppress glucose reabsorption in the proximal tubule of the kidney
  • Resulting in excretion of glucose in the urine and improvement of insulin resistance
  • Improvement in hyperglycemia
  • SGLT-2i can inhibit the development of NAFLD
  • Improve histological hepatic steatosis or steatohepatitis in experimental animal models
  • Visceral fat-dependent effects and inhibition of de novo lipogenesis in the liver
  • Reduce the risk of cardiovascular death or hospitalization in patients with HFrEF with or without type 2 diabetes mellitus (T2DM)
    • DAPA-HF, EMPEROR-Reduced, EMPULSE , EMPIRE-HF, SOLOIST-WHF , and CANVAS trials
    • SGLT-2i has become a mainstay in the treatment of HFrEF and HFpEF.
  • Meta-analysis, including 1950 patients, evaluated liver structure and function in patients taking SGLT-2i with placebo or other oral antidiabetic drugs
    • Decrease in liver function tests (LFT)
      • Alanine and aspartate aminotransferases and gamma-glutamyl transferase,
    • Decrease in liver steatosis
  • Meta-analysis showed that SGLT-2i also
    • Reduced liver fat content
    • Improved LFT in patients with NAFLD, as estimated by cardiac magnetic resonance proton density fat fraction
  • Findings imply that SGLT-2i may be an effective treatment for patients with both NAFLD and HFrEF.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

SGLT2 inhibitors



Salmon, tuna, and cod



Salsalate

  • A non-steroidal anti-inflammatory drug
  • Efficacious in reducing liver fat levels.

Non-alcoholic fatty liver disease patients

  • 1 of three groups consecutively over 12 months
    • Placebo for 2 months,
    • Low dose salsalate for 4 months
    • High dose salsalate for 8 months
  • Analysis showed decreased noninvasive markers of hepatic fibrosis at 4 months
    • On both doses of salsalate compared to baseline (placebo) noninvasive marker.
  • 48 participants completed the study
    • Non-invasive marker declined by 13.6% in the placebo group
    • 24.4% in the low dose salsalate group
    • 30.5% in the high dose salsalate group.
  • Weight decreased 5%, 14%, and 17%, respectively, for placebo, low dose, and high dose salsalate groups at 12 months (p=0.04)
  • Body mass index in all groups
    • Highly correlated with non-invasive markers of hepatic fibrosis (r=-0.49 to -0.60 p<0.001).
  • Non-invasive markers associated with hepatic fibrosis improved when weight loss was sustained.
  • Salsalate
    • Non-toxic and well-tolerated
    • Can improve noninvasive markers associated with hepatic fibrosis in NAFLD patients
    • Improve weight and body mass index.
  • gi.md/test-colonoscopy/is-it-possible-to-reverse-non-alcoholic-fatty-liver-disease

Short-term clinical trials

  • Salicylates exist in 2 different forms
    • Prototypical acetylated form aspirin
    • Nonacetylated form salsalate
  • Aspirin
    • Inhibits NF-?B
    • Also inhibits cyclooxygenase enzymes
      • Alterations in bleeding time, platelet aggregation, and gastric irritation
      • May cause side effects especially at increased dosages
  • Salsalate
    • Used to treat inflammatory conditions, such as rheumatoid arthritis, osteoarthritis, and other rheumatologic conditions
    • Only weakly inhibits the cyclooxygenase pathway secondary to the lack of an acetyl group
    • But it is a strong inhibitor of the NF-?B pathway
      • Decreasing the production of IL-6, TNF-alpha, and CRP
      • Decreasing insulin resistance
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4105730/

Salvianolic Acid

  • Prevents the pathological progression of hepatic fibrosis in high-fat diet-fed and streptozotocin-induced diabetic rats.

Sarpogrelate

  • Effectively decreased hepatic TG accumulation in mice
  • Closely resembling the effects of genetic deletion of Htr2a in the liver and Tph1 in the gut
  • Sarpogrelate treatment resulted in
    • Decreased expression of genes involved in lipogenesis
    • Genes involved in FA uptake, FA oxidation, and VLDL secretion were not changed in the liver
    • Gained less BW upon HFD
    • Their glucose tolerance was improved
    • Insulin tolerance was not affected
  • Crown-like structure in eWAT were decreased in HFD-fed mice treated with sarpogrelate
    • As compared to vehicle-treated HFD-fed mice
  • Results demonstrate that selective HTR2A antagonist can prevent hepatic steatosis in HFD-fed mice
  • d-nb.info/1173570659/34

Scoparone PPAR-gamma upregulation

  • Improved hepatocytes viability
  • Scoparone, an androstane receptor ligand
    • Improve the viability of Sprague-Dawley rat hepatocytes preserved in Euro-Collins solution
  • Vasodilator properties,
  • Enhancing the production of prostacyclin
    • Resulting in platelet aggregation
  • Scoparone, along with a combination of
    • Chlorogenic acid,
    • Rhein,
    • Geniposide
    • Emodin
  • Are the main components of a traditional Chinese medicine formula
    • Described to enhance adiponectin
    • Upregulate PPAR-gamma
    • Resulting in reversal of hepatocyte steatosis
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext


Organic selenium

  • Ameliorates non-alcoholic fatty liver disease
    • Through 5-hydroxytryptamine/bile acid enterohepatic circulation in mice
  • Organic selenium experienced a reduction in
    • Hepatic 5-hydroxytryptophan (5-HT) contents
    • Downregulation in the expression of tryptophan hydroxylase 1 (TPH1) and 5-HT receptor 2A/2B/3A.
    • Less TPH1/5-HT in the duodenum
    • Decreased the bile acid (BA) concentrations in gut contents
    • Downregulated the expression of hepatic CYP7A1
    • Upregulated the expression of hepatic Farnesoid X-activated receptor (FXR)
  • www.sciencedirect.com/science/article/pii/S1756464623001962
  • Selenium
  • Helps to fight against free radical damage and to reduce inflammation in the body.
  • Required for the production of glutathione
    • Powerful antioxidant in the liver
  • Selenium strengthens the detoxification pathways of the liver
  • Helps to fight all viral infections, including hepatitis.
  • www.liverdoctor.com/top-sellers/livatone-plus.html

Study adults from the 2017-2018 National Health and Nutrition Examination Survey

  • Subjects with excessive alcohol consumption and hepatitis B or C infection were excluded
  • Liver stiffness and steatosis were detected by transient elastography
  • Dietary selenium intakes and blood selenium concentrations were included as exposures
  • selenium intakes (tertile 3 vs. tertile 1) were
    • Positively associated with
      • Liver stiffness in females (odds ratio (95% confidence interval): 2.64 (1.88-3.70))
      • Liver steatosis overall (1.54 (1.20-1.97))
        • In males (1.55 (1.06-2.26))
  • Higher blood selenium concentrations (tertile 3 vs. tertile 1)
    • Positively associated with liver steatosis overall (1.33 (1.02-1.76))
      • In males (1.56 (1.13-2.16))
  • Adjustment for obesity, the abovementioned associations remain significant
    • Between dietary selenium intakes and
      • Liver stiffness in females (2.29 (1.69-3.12))
      • Liver steatosis overall (1.37 (1.01-1.86))
    • Blood selenium concentrations and liver steatosis in males (1.67 (1.25-2.21))
  • Dose-response analysis showed that the abovementioned associations were linear
  • Dietary selenium intakes meeting the recommended daily allowance (na 55 ug/day a výše)
    • were not associated with liver stiffness (0.99 (0.62-1.55)) and steatosis (1.01 (0.69-1.49))
  • Higher dietary selenium intakes and blood selenium concentrations
    • Were positively associated with liver stiffness and steatosis
    • Obesity may partially account for the observed associations.
  • pubmed.ncbi.nlm.nih.gov/34478060/

Studie NHANES 2017–18




Semaglutide



SGLT2 inhibitors

Tofogliflozin

  • Significantly improved the fibrosis scores, steatosis, hepatocellular ballooning, and lobular inflammation

Empagliflozin plus diabetes therapy

  • Better-improved liver fat in NAFLD patients with diabetes

Dapagliflozin and omega-3 carboxylic acids

  • Reduced liver fat

Ipragliflozin + diabetes therapy

  • Reduced liver steatosis in NAFLD patients with diabetes

Empagliflozin

  • Associated with reduction of ALT, liver stiffness and controlled attenuation parameter in patients with NAFLD and diabetes

Luseogliflozin

  • Improved liver-to-spleen ratio and liver fat in NAFLD patients with diabetes

Dapagliflozin and pioglitazone

  • Significantly increased liver-to-spleen ratio
  • Only dapagliflozin decreased visceral fat area in patients with NAFLD and diabetes

Ipragliflozin


Shiitake mushrooms

  • Great source of plant-based choline.
  • One cup (145 grams) of cooked shiitake mushrooms
    • Provides 116 mg, or 21% of your daily needs
  • Rich in nutrients like vitamin B5, selenium, and copper, benefit your immune health.
  • Study in 52 healthy adults
    • Eating 5 or 10 grams of shiitake mushrooms daily for 4 weeks
      • Reduced inflammatory markers like C-reactive protein (CRP)
    • Increased production of important immune cells and secretory immunoglobulin A (sIgA)
  • www.healthline.com/nutrition/foods-with-choline


Silkworm, Bombyx mori,

  • Contains beneficial components such as protein, minerals, amino acids and omega-3.
  • Technique to produce silkworms in an easy to eat Hongjam.
  • Inhibitory effect of Hongjam (50, 100, and 300 mg/kg body weight) on ethanol liver damage was investigated.

Male Sprague-Dawley rats for 4 weeks


Simtuzumab

  • Monoclonal antibody
  • Targeting lysyl oxidase-like 2 (LOXL2)
    • Key matrix enzyme in collagen formation
    • Highly expressed in the liver

Phase II trial in both cirrhotic and non-cirrhotic subjects with NASH


Sinigrin and allyl-isothiocyanate

  • Sinigrin is major component of commonly consumed cruciferous vegetables
    • Horseradish and wasabi
  • Degradation product allyl-isothiocyanate
    • Responsible for the characteristic pungent taste
  • Sinigrin to inhibit the growth of several types of cancer cells
    • Prevent the proliferation of liver tumour cells, inducing apoptosis and gradually restoring liver functions
  • Allyl-isothiocyanate
    • Can improve mitochondrial respiration efficiency
    • Reducing, at the same time, metabolic dysfunctions
  • Evaluated in muscle cells
    • Higher mitochondrial activity after allyl-isothiocyanate treatment
    • Increases in mitochondrial membrane potential, in mtDNA content and in respiratory capacity
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm

Sirtuins

  • Family of proteins that act as NAD-dependent deacetylases
  • Three sirtuins are exclusively located in the mitochondrial compartment
    • SIRT3, -4 and -5
  • Main target of resveratrol appears to be SIRT1
  • SIRT1 plays an important role in the regulation of metabolism
    • Stimulate both mitochondrial biogenesis and energetic metabolic fluxes
      • Via allosteric post-translational modifications of key enzymes
  • Modulation of NAD+ concentration
  • Significant portion of the cellular NAD+ pool is concentrated in the mitochondria
  • resveratrol can induce a mitochondrial complex I-dependent increase in NADH oxidation
    • Resulting in sirtuin activation in hepatocytes
    • Obtained in different experimental models
      • In vitro studies of isolated enzymes and HepG2 cells treated with resveratrol
      • In vivo study of an aging model of mice fed with resveratrol
  • Complex I activation increased the mitochondrial NAD+/NADH ratio
    • Higher NAD+ concentration initiated a SIRT3-dependent stimulation of the mitochondrial substrate supply pathways
  • mitochondrial complex I activity
    • May be involved in fatty liver through at least two mechanisms
      • A ROS-dependent mechanism - related to the control of complex I activity
      • ROS-independent mechanism - regulation of the ratio NAD+/NADH
  • Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23(23): 4146-4157 [PMID: 28694655 DOI: 10.3748/wjg.v23.i23.4146] www.wjgnet.com/1007-9327/full/v23/i23/4146.htm


Solithromycin

  • Macrolide antibiotic,

Currently in a phase II trial (NCT02510599)


Soybeans


Špenát


Spironolactone and vitamin E


Spironolactone

  • Patients with NAFLD and HFrEF may experience beneficial outcomes with the use of aldosterone antagonists
  • Spironolactone effectively improves the accumulation of triglycerides in the liver,
  • Reduces inflammation, and downregulates gluconeogenic and lipogenic gene expression

Spironolactone and vitamin E

  • Appears to have a positive effect on serum insulin levels in individuals with NAFLD
  • Patients with HF and reduced ejection fraction may benefit from the use of MRA such as spironolactone
    • Reduce mortality when administered at low doses of 25 mg to prevent hyperkalemia
  • ATHENA-HF Trial found that a high dose of spironolactone or eplerenone
    • May be a safe and effective treatment option for patients with HFrEF
      • Because it is associated with a reduction in NT-pro brain natriuretic peptide (BNP) levels
      • Reduction in body weight,
      • Improved symptoms of HF, such as dyspnea and fatigue
      • By reducing myocardial fibrosis and improving ventricular function
  • RAAS inhibitors, regardless of dose, may be particularly beneficial in patients with HFrEF
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/


Spirulina fusiformis

  • Protects against chemical-induced genotoxicity in mice [1]
  • By increasing the activity of cellular antioxidant enzymes
    • Superoxide dismutase
    • Catalase
    • Glutathione peroxidase [1]

Spirulina maxima - cyanobacterium

  • Experimentally proven to possess in vivo and in vitro hepatoprotective properties
  • Maintain the liver lipid profile
  • Hypolipidemic effects were also shown
  • As a food supplement
  • High content of proteins with essential amino acids
  • Carotenoids
  • B-vitamin complex
  • Minerals and
  • Linolenic
  • Omega-3 and omega-6 fatty acids
  • Rat hepytotxicity model
    • Diet with 5% Spirulina maxima
      • Decreases AST, TAG, CH, fFA, indicators for lipoperoxidation [1]
  • Its high C-phycocyanin content
    • Inhibits pancreatic lipase activity
    • Act together with glycolipid hemoglobin (Hb)-2,
      • Decrease in jejunal cholesterol absorption
      • Decrease ileal bile acid reabsorption [1]
    • This hypothesis does not explain all the physiopathological changes observed among patients

Statins

  • HMG-CoA reductase inhibitors
  • Plasma lipid-lowering abilities
  • NAFLD alone is an independent risk factor for cardiovascular disease

Cohort of 1201 Europeans who underwent liver biopsy for suspected NASH

  • Provide protection from steatosis (P = .004),
  • Protection from steatohepatitis (P < .001), and stage F2-F4 fibrosis (P = .017)

A small, prospective but uncontrolled study


Statins

  • Safe for patients with NAFLD across the disease spectrum
    • Including those with advanced liver disease
  • Lead to a demonstrable reduction in cardiovascular morbidity and mortality
  • Can impair insulin sensitivity and secretion by pancreatic beta-cells and increase insulin resistance in the peripheral tissues
  • Statins may also contribute to statin-induced T2DM
  • Statin use is associated with a significant reduction in cardiovascular mortality and morbidity (??)
  • Rosuvastatin
    • Did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic HF
    • It did reduce the number of cardiovascular hospitalizations
-
www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/


Stearoyl-CoA desaturase (SCD) inhibice

  • Enzyme that catalyses the rate-limiting step in the synthesis of monounsaturated fatty acids
    • Such as oleic acid
  • Located in the endoplasmic reticulum

Deficiency (or inhibition) of the SCD-1 isoform

  • Associated with decreased liver steatosis
  • Improved insulin sensitivity

Obese subjects with NASH


Probiotic combination + omega-3 fatty acids "Symbiter Omega"

  • In NAFLD: a randomized clinical study 48 patients
  • "Symbiter Omega"
    • Probiotic biomass supplemented with flax and wheat germ oil 250 mg of each
    • Omega-3 fatty acids 1-5%
  • Or placebo for 8-weeks
  • In probiotic-omega group
    • FLI significantly decreased from 83.53±2.60 to 76.26±2.96 (P<0.001)
    • While no significant changes were observed in the placebo group (82.86±2.45 to 81.09±2.84; P=0.156).
  • Probiotics with omega-3 lead to significant
    • Reduction of serum gamma-glutamyl transpeptidase,
    • triglycerides,
    • Total cholesterol.
    • Chronic systemic inflammatory markers after intervention decrease significantly only in Symbiter Omega group
      • IL-1beta (P=0.029), TNF-apha (P<0.001), IL-8 (P=0.029), IL-6 (P=0.003), and INF-gamma (P=0.016).
  • www.semanticscholar.org/paper/Beneficial-effects-of-probiotic-combination-with-in-Kobyliak-Abenavoli/e058761149a6378e938a0d22e78f98674dfb8629


Synbiotics

  • National Nutrition & Food (Iran)

Phase 2/3 Gut microbiome Patients with NAFLD and elevated liver enzymes


Taurine


Taurin (2-aminoethanesulfonic acid)

  • Protect the liver from various liver injuries
  • Relieve lipid profile
  • taurine can prevent or cure ALD, reduce fat deposition, but the mechanism remains unclear

ALD rat model was established by administration of alcohol, pyrazole and high fat diet.

  • 2% taurine was administered at the same time or after ALD model establishment.
  • Results:
    • Serum ALT, AST, serum and hepatic TC, TG and LDL-C were higher, HDL-C in ALD model rats was lower than normal rats
  • taurine can
    • Prevent and repair hepatic injury of ALD rats
    • Balance lipid metabolism indexes in the liver
  • Mechanisms may involves in the regulation of related enzymes and transcriptional regulators participated in lipid metabolism.
  • Taurine-in-Tang-Yang/175ab14b25547bd10cbb7b4bca4e0c43c62dc2b3">www.semanticscholar.org/paper/Preventive-or-Curative-Administration-of-Taurine-in-Tang-Yang/175ab14b25547bd10cbb7b4bca4e0c43c62dc2b3
  • Obtained through diet
  • Endogenously synthesized from methionine and cysteine
  • Small sulfur-containing amino acid
  • Does not encode for protein
  • Widely exists throughout the body
    • Platelets, leukocytes and heart, retina, liver, brain etc. (Lambert et al., 2015, Wen et al., 2019)
  • Antioxidation,
  • Anti-inflammation,
  • Osmoregulation,
  • calcium homeostasis,
  • Bile salt formation
  • Central nervous system function etc. (Lambert et al., 2015)

24 h urinary taurine levels

  • Marker of dietary taurine intake
  • Highly significant inverse relationship to the values of
    • Body mass index,
    • Blood pressure,
    • Total cholesterol (TC)
    • Atherogenic index
  • Dietary taurine may be important for metabolic syndrome prevention (Chen et al., 2016, Yamori et al., 2010).
  • Taurine protect the liver from various liver injuries
  • Improve lipid profiles.
  • taurine may have beneficial effects on AFLD and NAFLD.
  • taurine level was decreased in liver cirrhosis,

Taurine supplement prevented steatosis and steatohepatitis in AFLD and NAFLD

  • Induced by high-fat/cholesterol diet in experimental animals (Chang et al., 2011, Chen et al., 2009, Murakami et al., 2018, Tang et al., 2019, Wu et al., 2015, Yamamoto, 1996)

Taurine transporter knockout mice

  • Developed chronic liver disease characterized by
    • Fibrosis, inflammation and hepatocyte apoptosis (Warskulat et al., 2006).
  • All these suggest that high level of dietary taurine may protect against AFLD and NAFLD.
  • Homeostasis disruption of lipids metabolism in the liver
    • Is most likely to be responsible for the early stage of FLD
  • taurine plays a role in alleviating hepatic steatosis
    • By lowering the levels of triglycerides (TG) and cholesterol
    • Chang et al., 2011, Chen et al., 2009, Gentile et al., 2011, Hammes et al., 2012, Miyata et al., 2020a, Murakami et al., 2018, Pushpakiran et al., 2005, Tang et al., 2019, Wu et al., 2015

In vitro experiment

  • 1 mM taurine for 24 h
  • Caused 11% decrease of TG in HepG2 cells

In NAFLD animals induced by high fat diet or high fat/cholesterol diet or high sugar diet

  • taurine reduced liver TG by 16–31%
  • 0.7% taurine water (for 4 weeks)
    • Is an effective dose for diet-induced NAFLD

Tunicamycin-induced NAFLD mice

  • Liver TG decreased by 86% after drinking 2% taurine water for 11 days

Mice lacking farnesoid X receptor (FXR)

  • Often used as a genetic model for FLD because they exhibited
    • Hepatomegaly, hepatic steatosis and hepatic inflammation (Miyata et al., 2020b)
  • FXR-null mice, after drinking 0.5% taurine water for 4 weeks
    • Serum and hepatic TG decreased by more than 50%
  • taurine concentration in liver but not in serum increased significantly (Miyata et al., 2020a)
  • www.sciencedirect.com/science/article/pii/S1756464620305752
  • Taurine is a sulfur-containing-beta-amino acid

Male C57BL/6J mice fed a high-fat diet (HFD)

  • Supplemented with 2% (w/v) or 5% (w/v) taurine for 12 weeks
  • Twelve weeks of supplementation with an HFD increased the hepatic lipid levels and oxidative stress as well as the body weight and liver weight
  • Taurine significantly suppressed these changes
    • Accompanied by a decrease in the hepatic level of thiobarbituric acid-reactive substances (TBARS)
    • Suppressed the HFD-induced reduction of the enzyme activity of
      • Hepatic superoxide dismutase
      • Catalase
    • The reduction of the hepatic level of reduced glutathione and ATP

In HepG2 cells

  • taurine suppressed the fatty acid-induced lipid accumulation, production of reactive oxygen species and TBARS level, and amelioration of the fatty acid-induced disruption of the mitochondrial membrane potential.
  • taurine was effective in alleviating hepatic steatosis by reducing oxidative stress.
  • Taurine may be of therapeutic value in reducing the risks associated with NAFLD.
  • pubmed.ncbi.nlm.nih.gov/29946793/

Randomised clinical trial: oral taurine supplementation versus placebo

  • Reduces muscle cramps in patients with chronic liver disease
Helen Vidot, Erin Cvejic, Sharon Carey, Simone Irene Strasser, Geoffrey William McCaughan, Margaret Allman-Farinelli, Nicholas Adam Shackel





Telmisartan

  • 40 mg x placebo
    • Reduced free fatty acid level and increased liver-to-spleen ratio in diabetic patients with NAFLD
  • Telmisartan had similar effects to vitamin E in NAFLD histology
  • Telmisartan 40/80 mg
    • Improved NAFLD activity score and fibrosis in NASH
  • Telmisartan and olmesartan
    • Improved HOMA-IR and ALT levels Before-after comparison Quasi experimental
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Thiazolidinediones (TZDs) - PPARgamma agonists

  • Extensively used in diabetes as insulin sensitizers
  • Effective in the treatment of NASH

Pioglitazone

PIVENS trial: Pioglitazone + vitamin E and placebo

  • With improvement in NASH histology
  • Trend towards improvement in NASH histology with pioglitazone compared to placebo (34% vs. 19%; P = .04)
    • Did not reach the study's goal (P = .025)
  • Significant reduction in the serum ALT and AST and hepatic steatosis and lobular inflammation
    • Compared to placebo (P < .001), (P < .001) and (P = .004)
  • no significant improvement in fibrosis with pioglitazone compared to placebo
  • Weight gain (which also occurred in the PIVENS study)
  • Risk of congestive heart failure previously linked to this drug
    • May limit its use in the treatment of NASH

Saroglitazar - Dual PPAR?/gamma agonist

  • Treat diabetic dyslipidemia in India
  • Result in a significant decrease in ALT levels in NAFLD and biopsy-proven NASH
  • Further clinical studies are needed in this drug to confirm this initial success.
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302

Thiazolidinediones

  • Peroxisome proliferator-activated receptor-g activators in adipose, muscle, and liver tissues
    • Resulting in a decrease in glucose production
    • Subsequent increase in glucose utilization
  • Thiazolidinediones
    • Particularly pioglitazone, have proven efficacious in patients with NAFLD/NASH
  • Thiazolidinediones
    • Should be avoided in patients with reduced LVEF

Rosiglitazone

  • Increase the risk of MI and HF,
    • Whereas pioglitazone decreased the risk of major adverse cardiovascular events, such as MI and stroke, but increased the risk of HF
  • Patients with T2DM with New York Heart Association functional class I-II CHF and reduced LVEF
    • Were randomized to 52 wk of treatment with rosiglitazone
  • Significantly more confirmed events of new or worsening edema and increased HF medication in the rosiglitazone group

Pioglitazone

  • Was associated with higher rates of HF hospitalization in a smaller randomized controlled trial of participants with more severe symptomatic HFrEF than placebo
  • A recent meta-analysis compared placebo and pioglitazone
    • Significantly improved steatosis grade, inflammation grade, and ballooning grade
    • Fibrosis stage, there was no significant improvement in pioglitazone compared with placebo
  • Pioglitazone
    • Significantly reduced
      • Fasting blood glucose,
      • Glycosylated hemoglobin,
      • Serum alanine, aspartate aminotransferase levels
  • Systematic review showed that pioglitazone
    • Consistently improved histological parameters and normalized liver transaminases
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Tirzepatide

  • Novel medication for the treatment of T2DM
  • Dual glucose-dependent insulinotropic polypeptide and a GLP-1 receptor agonist
  • Promising results in ongoing clinical trials
    • For T2DM
    • Improving body weight and steatosis
  • Proti dulaglutide on NAFLD biomarkers and fibrosis in patients with diabetes mellitus
    • Higher tirzepatide dose significantly decreased NAFLD biomarkers and increased adiponectin levels
  • SURPASS-3, using magnetic resonance imaging, demonstrated that tirzepatide
    • Significantly reduced liver fat content, visceral adipose tissue volume, and abdominal subcutaneous adipose tissue
  • Efficacy and safety of tirzepatide in patients with HFpEF and obesity are being assessed
  • No current data supports the use of tirzepatide in patients with HFrEF.
  • Studies on patients with HFrEF are recommended.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Turmeric (Curcuma longa):

  • Rahmani AH, Alsahli MA, Aly SM, et al. Therapeutics role of curcumin on lipid peroxidation and antioxidant status in hyperlipidemic rats. Journal of Physiology and Biochemistry, 2019. DOI: 10.1007/s13105-019-00674-5

Effect of Turmeric Supplementation on Blood Pressure and Serum Levels of Sirtuin 1 and Adiponectin in Patients with Nonalcoholic Fatty Liver Disease: A Double-Blind, Randomized, Placebo-Controlled Trial

  • Ali Kalhori,1 Maryam Rafraf,2 Roya Navekar,corresponding author2 Aida Ghaffari,3 and Mohammad Asghari Jafarabadi4
  • Total of 46 eligible patients with NAFLD (BMI, 25.0~39.9 kg/m2)
  • Turmeric and placebo groups using block randomization
    • Tumeric group (n=23) was administered 3,000 mg/d turmeric powder in six 500-mg capsules for 12 weeks
    • Placebo group (n=23) was administered six placebo capsules/d for 12 weeks
  • Serum SIRT1 levels increased significantly in the turmeric group
  • Participants in the turmeric group exhibited
    • Lower weight, BMI, and systolic blood pressure after 12 weeks
  • Efficacy of turmeric might increase with long-term use at higher doses.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC9007706/
  • Turmeric is the powdered rhizome of Curcuma longa
    • Member of the Zingiberaceae family (Maheshwari et al., 2006)

Curcuminoids

  • Core components of turmeric extract
  • Safe compounds for human consumption
  • Increasing adiponectin and SIRT1 levels
  • Improving insulin resistance
  • Reducing tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1beta levels (Ganjali et al., 2017).
  • Protective agents (antioxidants) against hypertension (Kukongviriyapan et al., 2016)

In vivo rat model study

  • curcumin supplementation was reported to improve anthropometric measures and hepatic enzyme levels (Kyung et al., 2018). Panahi et al. (2017)
  • curcumin supplementation exerted protective effects against liver fibrosis and cirrhosis.

Randomized, double-blind, placebo-controlled trial

NAFLD aged 20 to 60 years from Sheikhol-Raees Clinic in Tabriz, Iran

  • C. longa L. rhizomes washed and dried at room temperature and subsequently crushed using a powder mixer
    • Filled in 500-mg capsules
  • The turmeric group received 3,000 mg/d turmeric
    • In the form of six 500-mg capsules/d, for 12 weeks
    • Two capsules ingested before each main meal
  • Placebo group received six placebo capsules/d for 12 weeks
  • Analyses suggest the potential efficacy of turmeric in improving SIRT1 levels in patients with NAFLD.
  • Efficacy of turmeric
    • Includes a combination of different compounds
  • Supplementation with 3,000 mg/d turmeric
    • Was not associated with any side effects

Previous clinical trials efficacy of up to 1,500 mg/d curcumin extract

Curcumin

  • Component of turmeric
  • Increase the level and activity of adenosine monophosphate-activated protein kinase
  • Can activate nicotinamide phosphoribosyltransferase (NAMPT)
    • NAMPT produces NAD+
      • Helps in the activation of SIRT1 - NAD+-dependent enzyme (Zendedel et al., 2018)
  • curcumin
    • Increased SIRT1 levels
    • Decreased mitochondrial oxidative stress in rat cardiomyocytes
    • Can activate peroxisome proliferator-activated receptor (PPARgamma) gene expression
      • Might be involved in the translocation of hepatic triglycerides and free fatty acids to adipose tissue,
        • Thereby ameliorating hepatic fat accumulation (Skat-Rordam et al., 2019).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC9007706/

2021 study 64 people with NAFLD

  • 2 grams of turmeric or a placebo
  • Every day for 8 weeks
  • Liver enzymes dropped significantly in the turmeric group
  • triglycerides and cholesterol also declined in the turmeric group

2019 systematic review assessed five prior trials of turmeric for NAFLD

  • Each of the trials was small,
  • 3/4 trials with data on turmeric or curcumin compared to baseline showed reductions in liver enzymes and the severity of NAFLD.
  • 2/4 placebo-controlled studies showed significant reductions in the liver enzymes ALT and AST with turmeric or curcumin compared to placebo.
  • 1/4 placebo-controlled trials used turmeric instead of curcumin
    • Study did not show improvements in liver enzymes or NAFLD severity
    • curcumin, rather than turmeric, could be the more important supplement

Ursodeoxycholic acid

  • Mobilizes hepatotoxic bile acid from their pool [1]
  • Pravděpodobně má i antibakteriální vliv ve střevě a může ovlivnit tzv. SIBO a snížit produkci bakteriálních toxinů, které mohou přispívat k toxicitě vůči játrům = moje domněnka

Eggs

  • Eggs are one of the best sources of choline
  • 1 egg providing 147 mg
  • 2 eggs per day covers 54% of the Recommended Daily Intake (RDI)
  • choline content of an egg is almost entirely concentrated in the yolk
    • 680 mg of the nutrient per 100 grams of egg yolk
    • 1 mg per 100 grams of egg white
  • Important to eat the whole egg to get the most choline
  • Natural choline in eggs
    • May be better absorbed than forms of the nutrient found in dietary supplements.
      • choline in eggs is bound to a type of fat called phospholipids
        • Hydrophilic (having an affinity to water) and hydrophobic (having an aversion to water) components
  • www.healthline.com/nutrition/foods-with-choline#1.-Whole-eggs

Vildagliptin

  • Alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades
  • pubmed.ncbi.nlm.nih.gov/35671811/

Vitamin E


Vitamín E a C

A study published in 2006

  • Oxidative stress is one of the initiating factors of lipid peroxidation
    • Subsequent hepatocellular damage in NAFLD
  • Antioxidants such as vitamin E
    • Might have beneficial effects against the disease
  • Vitamin E
    • Four tocopherols (alpha, beta, gamma and delta-tocopherols)
    • Four tocotrienols (alpha, beta, gamma and delta-tocotrienols)
    • Present in different nutrients
  • Major dietary sources of vitamin E are
    • Vegetable oils,
      • Safflower
      • Sunflower
  • Major lipid- soluble chain-breaking antioxidant
    • May act as a scavenger of hydroxyl, peroxyl, and superoxide radicals
      • Terminate the oxidation of polyunsaturated fatty acids
      • Protecting against plasma lipid and low-density lipoprotein peroxidation
      • Preventing the further oxidation of PUFAs in the membrane
  • Potential alternative for the treatment of NAFLD and NASH for its non-antioxidant effects

Diet-induced NASH

  • Vitamin E can reduce inflammation,
  • Improve hepatic fibrosis,
  • Attenuate hyperinsulinemia,
    • Without affecting the insulin signaling
  • Induction of adiponectin expression,
  • Reduction of the inflammatory pathway,
  • Regulation of macrophage polarization

Prospective, cross-sectional registry-based study

  • Children with NAFLD have a diet low in vitamin E
    • May contribute to the pathophysiology of the disease

Study on efficacy of Vitamin E in the management of NAFLD 2004, Vajro et al.

  • vitamin E (400 mg/day × 2 months, 100 mg/day × 3 months) x controlled group of children with suspected NAFLD
  • Showing no benefits in the use of the antioxidant therapy

Italian group of Nobili et al. study

  • Nutritional program alone
  • Or combined with alpha-tocopherol (600 IU/day) and ascorbic acid (500 mg/day)
  • In biopsy-diagnosis NAFLD children (n = 90)
  • After 12 months, they found
    • Diet and physical activity seem to lead to a significant improvement of liver function beyond antioxidant treatment.

Extension study in 53 patients (age 5.7–18.8 years)

  • Effect of lifestyle intervention plus alpha-tocopherol and ascorbic acid (same doses that in the original study) (n = 25) or placebo (n = 28) for 24 months
  • At the end of the study, they found:
    • Lifestyle intervention was associated with
      • A significant improvement in liver histology
      • Laboratory abnormalities
      • With no differences in the group that received alpha-tocopherol plus ascorbic acid

Double blind, placebo-controlled clinical trial

  • vitamin E + metformin in children and adolescents with NAFLD diagnosed by biopsy
  • 173 patients (aged 8–17 years) for 96 weeks
  • Found no significant improvement in ALT
  • There was an improvement in NAFLD activity score and hepatocellular ballooning score in the liver biopsies.

Cho et al. children with NAFLD

Reduction of the BMI through diet and exercise + vitamin E + ursodeoxycholic acid

  • Has greater effect on the improvement of hepatic biochemical profile
    • AST, ALT, AST/ALT ratio, alkaline phosphatase, total bilirubin and gamma-glutamyl transpeptidase
      • Compared to BMI reduction alone

44 overweight/obese children aged 10–17 years

  • Antioxidant supplementation for four months
  • There was a significant effect of antioxidant supplementation on
    • Antioxidant status
    • Oxidative stress
    • Liver transaminases were moderately improved in the treatment group x controls

Wang et al. vitamin E + lifestyle in 76 Chinese children (ages 10–17 years) with obesity and NAFLD

  • vitamin E was effective in reducing ALT
  • Lifestyle intervention was more effective

A systematic review and meta-analyses of randomized control trials adults and children published in 2019

  • vitamin E therapy provides significant biochemical and histological improvements
    • In adult patients with NAFLD,
  • Pediatric patients
    • Insignificant efficacy compared with placebo.

Some evidence exists against the use of Vitamin E

  • One study has shown daily administration of vitamin E increased
    • The risk of developing prostate cancer
  • Some studies related high-dose vitamin E supplementation
    • Increased mortality

2017 NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Non-alcoholic Fatty Liver Disease in Children

  • no currently available medications or supplements are recommended to treat NAFLD
    • Because of a lack of evidence

2018 American Association for the Study of Liver Diseases practice guidance

  • Supporting the use of vitamin E in children with biopsy-proven NASH
  • Safety and efficacy of vitamin E for the treatment of NAFLD, particularly in the pediatric population
    • Requires further studies before its use can be recommended in clinical practice
  • Kdyby takhle opatrní byli i u schvalování a prosazování mRNA vakcín proti COVID19 u dětí...
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/
  • Vitamin E shown to be effective in NASH in a successful pilot study

PIVENS trial comparing non-diabetic, biopsy-proven NASH patients

  • 800 IU/day of vitamin E (800 mg/day; n = 84) to patients receiving pioglitazone (30 mg/day; n = 80) and placebo (n = 83)
  • vitamin E was better than placebo
    • In reducing ALT levels (P < .001),
    • Liver steatosis (P0.005)
    • Inflammation (P = .02)
  • vitamin E effectively promoted resolution of NASH (43% vs. 19% in placebo; P = .001).
  • There was no improvement in the liver fibrosis score (P = .24)

TONIC trial performed in children and adolescents

  • Pooled data from the PIVENS trial and the placebo arm of the FLINT trial
    • Who received vitamin E supports the efficacy of vitamin E in diabetics as well
      • Irrespective of the status of diabetes
      • Histological features of the liver were markedly better in patients receiving vitamin E than in those who did not receive the medication
  • Prolonged use of this medication, especially at higher doses, may have unwanted influence mortality.
    • All-cause mortality was not supported by subsequent studies on the subject
  • Some studies have linked long-term use of vitamin E to
    • Increased risks of prostate cancer
    • Haemorrhagic stroke
  • Potential risks need to be considered in relation to the extent of disease activity (NASH) and the patient's health
  • Dose of 400 IU daily could be a solution in certain circumstances
  • onlinelibrary.wiley.com/doi/10.1111/liv.13302

Vitamin D:

  • Targher G, Bertolini L, Scala L, et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutrition, Metabolism, and Cardiovascular Diseases, 2007. DOI: 10.1016/j.numecd.2006.10.004

Vitamin D Generic

Study at University of Palermo (Italy) Patients with biopsy-proven NASH

University of Zurich (Switzerland) - Phase 2 Vitamin D receptor Patients with biopsy-proven NASH


Vitamin D

  • Broad spectrum of actions including immune modulation, cell differentiation and proliferation
  • Regulation of inflammation
  • Regulation of glucose and lipid metabolism
  • Appealing therapeutic target for NASH.
  • Dietary vitamin D2 or sunlight-derived D3 is metabolized to 25-hydroxyvitamin D in the liver
    • Before it is transported to the kidney where it is hydroxylated
      • To become the biologically active form 1a,25-dihydroxyvitamin D
  • 1,25(OH)2D binds to vitamin D receptors

Animal studies VDR knockout mice

  • Spontaneously develop liver fibrosis

A murine model with phototherapy

  • Increased 25 (OH)D and 1,25(OH)2D levels
    • Were able to reduce hepatocyte inflammation, fibrosis, and apoptosis compared to control
  • Insulin resistance improved, serum adiponectin increased, and inflammatory gene expression TNF-? and TFG-ß were reduced

Epidemiologic evidence

  • Patients with low vitamin D levels
    • Most susceptible to development of NASH

Meta-analysis

  • Patients with NASH were 26% more likely to have low levels of vitamin D compared to the control subjects

A small, double-blinded, placebo-controlled study

  • NASH patients to either 50,000 IU vitamin D or placebo every 2 weeks for 4 months
  • There were no significant differences between groups in liver enzymes, insulin sensitivity, or grades in hepatic steatosis.
  • Levels of hsCRP and malondialdehyde (MDA)
    • Both markers of lipid peroxidation, were decreased in patients given vitamin D
      • It may be useful to mitigate inflammation

Phase 2 trial and one phase 3 trial to evaluate whether vitamin D supplementation


St Mary’s thistle + B group vitamins + antioxidants + sulfur rich amino acids


Vitamin B12, folic acid and vitamin C

  • Required for the detoxification of chemicals in the liver

Xyloketal B - Xyl-B

  • Reverses Nutritional Hepatic Steatosis, Steatohepatitis, and Liver Fibrosis through Activation of the PPARa/PGC1a Signaling Pathway
  • A marine-derived natural product,

Mice fatty liver model

  • Administration of Xyl-B (20 and 40 mg·kg–1·day–1, ip)
    • Ameliorated the hepatic steatosis in HFD mice
  • Upregulation of a cluster of peroxisome proliferator-activated receptor-a downstream enzymes
    • Mainly related to fatty acid oxidation (FAO)
  • Expression levels of PPARa and PPARg coactivator-1a (PGC1a) were increased

Methionine-choline-deficient (MCD) mice hepatitis and liver fibrosis models

  • PPARa-mediated anti-inflammatory and antifibrosis effect of Xyl-B in
  • Histological features were improved
  • Inflammatory factors, adhesion molecules, as well as fibrosis markers were decreased after the treatment
  • Xyl-B ameliorated different phases of NAFLD
    • Through activation of the PPARa/PGC1a signaling pathway
  • pubs.acs.org/doi/10.1021/acs.jnatprod.2c00259

Avoid Eating Deep Fried foods

  • Increased risk of developing non-alcoholic fatty liver disease
  • fats in deep-fried foods can cause inflammation and damage to the liver cells.
  • Avoid eating fried foods like jalebi, samosa, or french fries
  • reversefactor.in/fatty-liver-disease-reverse

Gren tea

  • Two to three cups of green tea on a daily basis
  • Or 600 mg of supplemental green tea extract daily.
    • Catechins derived from decaffeinated green tea.
  • Some studies suggest that green tea and catechins derived from green tea
    • Can decrease intestinal fat absorption and storage
  • www.wikihow.com/Reverse-Fatty-Liver
  • Preventive Efficiency of Green Tea and Its Components on Nonalcoholic Fatty Liver Disease
  • Green tea contains abundant bioactive compounds possessing
    • Antioxidant, lipid-lowering, and anti-inflammatory effects,
    • Improving insulin resistance
    • Changing gut dysbiosis that can alleviate the risk of NAFLD

Summarized the studies of green tea and its components on NAFLD from animal experiments and human interventions

  • Available evidence suggested that tea consumption is promising to prevent NAFLD
Jie Zhou, Chi-Tang Ho, Piaopiao Long, Qilu Meng, Liang Zhang*, and Xiaochun Wan* Cite this: J. Agric. Food Chem. 2019, 67, 19, 5306–5317 Publication Date:March 20, 2019

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