MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Příčiny a rizikové faktory steatózy

5-hydroxytryptamine (5-HT) - serotonin periferní

  • Most peripheral 5-HTs are derived from enterochromaffin cells of the gut
  • 5-HT regulates hepatic fibrosis in hepatic stellate cells (HSCs)
    • By activating HSC-produced transforming growth factor (TGF)-signaling
  • Through the 5-HT2B receptor
    • 5-HT promotes gluconeogenesis in hepatocytes by increasing the activity of
      • Fructose 1,6-bisphosphatase (FBPase)
      • Glucose 6-phosphatase (G6pase)
  • 5-HT2B receptor signaling
    • Inhibits glucose uptake
      • By promoting the breakdown of glucose transporter 2 (GLUT2)
  • Activation of the sterol-regulatory-element-binding protein 1 (SREBP1) signaling pathway
    • By the 5-HT2A receptor
      • Increases lipogenesis in the liver
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8743581/

Alkohol

  • To, že je jaterní steatóza prvním stupněm poškození jater při nadměrném pití alkoholu, je už dlouho známé. [2]
  • Nealkoholová
    • Nepije vůbec nebo velmi málo (muž - max. do 40 g čistého alkoholu za den)
      • řada nemocných množství vypitého alkoholu správně nepřiznává
      • Individuální rozdíly vůči toxickému vlivu alkoholu
        • 40 g/den už být pro řadu lidí dávkou játra poškozující [2]
  • There is no such thing as an OK amount of alcohol for people trying to reverse NAFLD
    • Not even the standard drink per day for women or two drinks per day for men.

A study published in Gastroenterology

  • Alcohol significantly impacts disease progression in other forms of liver disease, including NASH.
  • There is no safe amount of alcoho
Rinella, a coauthor of the study

Amiodarone, valproate, tamoxifen, methotrexate

  • Underlying metabolic risk factors such as obesity and metabolic syndrome
    • May exacerbate their potential to cause DIHS and its progression

Some chemotherapeutic

Some antiretroviral agents

Some medications for hereditary homozygous hypercholesterolemia

  • Cause hepatic steatosis


Asociace

  • A fatty liver is linked to several other health conditions. Treat those issues and you can help reverse NAFLD, too. Conditions might include:
    • Diabetes
    • High cholesterol
    • High triglycerides (fat in the blood)
    • Sleep apnea
    • Polycystic ovary syndrome
    • Underactive thyroid, or hypothyroidism
    • Underactive pituitary gland, or hypopituitarism

Ketogenní dieta bez dostatku antioxidantů ve stravě

  • Mitochondrial adaptation during non-alcoholic fatty liver disease (NAFLD) include
    • Remodeling of ketogenic flux
    • Sustained tricarboxylic acid (TCA) cycle activity
    • Concurrent to onset of oxidative stress
  • Over 70% of obese humans have NAFLD
  • Ketogenic diets are common weight loss strategies

Mice (C57BL/6)

  • Were kept (for 16-wks) on either a low-fat, high-fat, or high-fat diet
  • Supplemented with 1.5X branched chain amino acids (BCAAs)
    • By replacing carbohydrate calories (ketogenic)
  • Ketogenic diet induced hepatic lipid oxidation and ketogenesis
  • Produced multifaceted changes in flux through the individual steps of the TCA cycle.
  • Higher rates of hepatic oxidative fluxes fueled by the ketogenic diet
    • Paralleled lower rates of de novo lipogenesis.
  • This metabolic remodeling
    • Did not improve insulin resistance
    • Induced fibrogenic genes and inflammation in the liver
  • Chronic "ketogenic environment," the hepatocyte diverted more acetyl-CoA away from lipogenesis toward ketogenesis and TCA cycle
    • Can hasten oxidative stress and inflammation
  • Chronic exposure to ketogenic environment during obesity and NAFLD
    • Has the potential to aggravate hepatic mitochondrial dysfunction
  • pubmed.ncbi.nlm.nih.gov/32918763/
  • A co dalšího jedly ty myši ? Měly zelené salátky a smoothie plné antioxidantů nebo měly nějaké sušené hnusy, ze kterých by onemocněl časem později každý?
  • Spalování tuků - lipolýza - stimulovaná rozvětvenými AMk samozřejmě generuje nějaké volné radikály. Pokud dieta se zvýšneou oxidací tuků a lačnění nemá člověka poškodit zvýšeným oxidačním stresem, je nutné mít dostatek antioxidantů ve stravě - obzvláště při hubnutí v tuku nebo steatoze jater. To je také důvod, proč záleží na tom, zda je dieta z přizené stravy nebo jen na principu sušených substrátů z pytlíku, kde bude komplexnícsh anxioxidantů málo. Metabolic Balance zástupci používají termín "Clean Keto versus Dirty keto."





CCl4


CD36 and fatty acid transport proteins (FATPs) upregulation


Cadmium (Cd)


Chemoterapeutika

Methotrexate, 5-fluorouracil, irinotecan, tamoxifen and l-asparaginase

  • Hepatotoxic phenotype known as "CASH" for "Chemotherapy-induced Acute Steatohepatitis"
  • Mechanism of toxicity
    • Essentially based on mitochondrial toxicity
  • Lesions are chronic
  • Often reversible when the treatment is stopped
  • Important to identify chemotherapies with steatosis or steatohepatitis as risk factors
    • Reinforce monitoring during treatment
  • Neo-adjuvant chemotherapy for metastatic colorectal cancer
    • Short duration of chemotherapy and a few-weeks delay between chemotherapy and surgery
      • Could reduce postoperative morbidity and mortality
  • pubmed.ncbi.nlm.nih.gov/32061473/

Microvesicular steatosis

Macrovesicular steatosis

Phospholipidosis

  • Drug-induced phospholipidosis (DIPL)
  • Benign condition
  • Appearance of intracellular accumulation of phospholipids and lamellar bodies
  • Microscopic subcellular structures induced by a variety of drugs
  • These cytosolic inclusions consist of concentric myelin-like structures
    • So-called lamellar bodies
    • Became the morphological hallmark of phospholipidosis
  • More than 50 novel chemical entities have been identified to induce phospholipidosis
    • Antibiotics,
    • Antidepressants,
    • Antipsychotics,
    • Antimalarial
    • Antiarrhythmic drugs
  • Amiodarone, fluoxetine, gentamicin, perhexiline and 4.4’-dieethylaminoethoxyhexestrol (DH)
  • www.elsevier.es/en-revista-annals-hepatology-16-articulo-drug-induced-fatty-liver-disease-an-S1665268119309482

Mitochondria dysfunction



Eplerenone

Na lidech

  • Study stopped early due to an unexpected increase in hepatic fat at 24 wk

In vitro a zvířata

  • Eplerenone on nonalcoholic steatohepatitis and metabolic syndrome in a mouse model
    • Eplerenone effectively ameliorated insulin resistance, blood pressure, and hepatic steatosis with fibrotic changes by inhibiting the inflammatory response in Kupffer cells and macrophages
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/


Ethanol-producing bacteria

  • Marra and Svegliati-baroni 2017
  • Ethanol also fulfills a role in the pathogenesis of MAFLD
  • Ethanol-producing K. pneumoniae
    • Present in up to 60% of MAFLD patients

Oral gavage of clinical isolates in mice

  • The NASH-promoting effects

Fecal microbiota transplantation

  • Ethanol-producing K. pneumoniae strain was selectively removed from the fecal transplant
    • The mice did not develop MAFLD (Yuan et al. 2019)
  • The NASH-promoting effects induced by K. pneumoniae
    • Part due to mitochondrial dysfunction (Chen et al. 2020)
      • Oxidative stress which is a hallmark of NASH (Buzzetti et al. 2016)
  • Liver-infiltrating T cells, neutrophils, macrophages, and B cells
    • Were more abundant in mice fed the ethanol-producing K. pneumoniae strain or ethanol (Yuan et al. 2019)
      • Indicating immune system activation
  • Presence of ethanol-producing K. pneumoniae in the gut can be considered as a risk factor for MAFLD
  • link.springer.com/article/10.1007/s00204-021-03069-1

FGF21

  • Hormone that plays an important role in regulating metabolic pathways
  • Mainly produced by the liver
  • Signaling is associated with NAFLD pathogenesis
  • FGF21 regulates lipid and glucose metabolism, which is correlated with CVD and HF
  • FGF21 may be a potential biomarker for prognosis prediction and as a treatment target in the future
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/


Glyphosate

  • Induced autophagy inhibition
    • Results in hepatic steatosis
      • Via mediating epigenetic reprogramming of PPAR? in roosters
  • Glyphosate (Gly)- most widely used herbicide

Rooster model combined with primary chicken embryo hepatocytes

  • Data showed that Gly exposure caused liver injury
    • With disrupted lipid metabolism in roosters
    • Manifested by significant serum lipid profile disorder and hepatic lipid accumulation.
  • Transcriptomic analysis revealed that PPARalpha and autophagy-related pathways
    • Played important roles in Gly-induced hepatic lipid metabolism disorders

Autophagy inhibition

  • Was involved in Gly-induced hepatic lipid accumulation
  • Confirmed by the effect of classic autophagy inducer rapamycin (Rapa)
  • Gly-mediated autophagy inhibition
    • Caused nuclear increase of HDAC3
      • Altered epigenetic modification of PPARalpha
        • Leading to fatty acid oxidation (FAO) inhibition
          • Subsequently lipid accumulation in the hepatocytes
  • Gly-induced autophagy inhibition evokes the inactivation of PPARalpha-mediated FAO and concomitant hepatic steatosis
Cai-Yu Lian 1, Sheng Wei 2, Zi-Fa Li 2, Shu-Hui Zhang 1, Zhen-Yong Wang 1, Lin Wang 3, PMID: 36906059 DOI: 10.1016/j.envpol.2023.121394


Hyperhomocysteinemia (HHcy)

  • Key risk factor in hepatic steatosis

Animal study mice

  • HHcy was induced in mice by giving DL-Hcy (1.8 g/L) in drinking water for 6 weeks
  • HHcy mice exhibited hepatic steatosis
    • With a notable increase in ceramide-related metabolites
      • Subsequent upregulation of ceramide synthesis genes such as Sptlc3, Degs2, Cer4 and Smpd4.
  • Omega-3 PUFA was simultaneously administered in HHcy mice through chow diet
    • 3.3% omega-3 PUFA supplement for 6 weeks
      • Significantly ameliorated Hcy-induced hepatic steatosis
  • The decrease in hepatic lipid accumulation
    • Due to reduced hepatic levels of ceramides,
      • Partly the result of the lower expression of ceramide synthesis genes, Sptlc3 and Degs2

In vitro study

Deficit vitamínu B6, B12, B9

  • Další rizikový faktor jaterní steatozy

Mutace MTHFR enzymu

  • Zhoršený metabolismus B9 (kyseliny listové) = rizikový faktor
Homocystein v krvi se dá změřit běžně v laboratoři



Immune response gene 1 deficiency

  • Aggravates high fat diet-induced nonalcoholic fatty liver disease via promotion of redox-sensitive AKT suppression
  • Nonalcoholic fatty liver disease (NAFLD)
  • Most common chronic liver disorder worldwide
  • Immune response gene 1 (IRG1) catalyzes the production of bio-active itaconate
  • Expression of IRG1 was significantly down-regulated in obesity-associated fatty liver

Genetic deletion of IRG1

  • Aggravated high fat diet (HFD)-induced metabolic disturbance, including
    • Obesity,
    • Dyslipidemia
    • Insulin resistance

IRG1 KO mice

  • HFD induced
    • More severe liver steatosis
    • Higher serum ALT and AST level
  • Altered expression of genes involved in
    • Lipid uptake, synthesis and catabolism.

RNA-seq and immunoblot analysis

  • Deficiency of IRG1 is associated with suppressed activation of AKT
    • A master metabolic regulator

IRG1/itaconate

  • Enhanced the antioxidative NRF2 pathway
  • Prevented redox-sensitive suppression of AKT

Supplementation with 4-octyl itaconate (4-OI)

  • A cell-permeable derivate of itaconate
  • Alleviated HFD-induced oxidative stress, AKT suppression and liver steatosis
  • IRG1 probably functions as a protective regulator
  • Might have potential value for the pharmacological intervention of NAFLD.
Xue Zhang 1, Ying Zhi 2, Xinyan Zan 2, Kerui Fan 2, Kun Chen 2, Shuang Zhao 2, Xinyi Dai 2, Longjiang Li 2, Yongqiang Yang 2, Kai Hu 3, Xianqiong Gong 4, Li Zhang 5 PMID: 36706797 DOI: 10.1016/j.bbadis.2023.166656


Imidacloprid


Inhibice autofagocytozy



Inhibice jaterní beta-oxidace



Intestinal PPR alpha

  • Genetic and environment overeating-induced increase of the gut absorptive capacity
  • lipids, intestinal PPARalpha knock-out or its pharmacological antagonism
    • Suppress intestinal crypt expansion
    • Shorten villi in mice and in human intestinal biopsies
    • Diminishing the postprandial triglyceride transport and nutrient uptake

Intestinal PPARalpha ablation

  • Limits systemic lipid absorption
  • Restricts lipid droplet expansion and PLIN2 levels
  • Improves the lipid metabolism
  • Reduces body adiposity and liver steatosis
  • Suggesting an alternative target for treating obesity.
  • pubmed.ncbi.nlm.nih.gov/34857752/


Intestinal inflammation

  • Increased in mice fed a high-fat diet (HFD; 60% fat calories),
    • Accompanied by altered composition of gut microbiota involved in the development of NAFLD

Klebsiella pneumoniae (K. pneumoniae)

  • Commensal Gram-negative bacterium of the Enterobacterales order
  • Can cause opportunist infections in the compromised (usually hospitalized) host (Paczosa 2016).
  • Alterations in gut microbiota may contribute to a series of diseases including
    • Type 2 diabetes,
    • Obesity
    • MAFLD (Abu-Shanab and Quigley 2010).
  • link.springer.com/article/10.1007/s00204-021-03069-1
Klebsiela je nově rozponána jako jedna z příčin SIBO


Lipotoxic lipids

Hepatic de novo lipogenesis (DNL)

Disruption of the intestinal barrier


MTP inhibitors and MTP inhibition

  • fat absorption may be reduced by inhibiting the activity of the microsomal triglyceride-transfer protein (MTP)
    • Involved in the formation and secretion of very light density lipoproteins (VLDL) and chylomicrons
  • Mtp gene is responsible for abetalipoproteinemia disease
  • MTP inhibitors, which are aimed at treating various conditions associated with excessive fat absorption
    • Major side effects including hepatic steatosis attributed to reduced MTP activity in both intestine and liver
  • People naturally deficient for MTP activity were shown to develop fatty livers
    • [Kane and Havel (1989); Disorders of the biogenesis and secretion of lipoproteins containing the apolipoprotein B. pp. 1139-1164 in: “The metabolic basis of inherited disease” (Scrivers et al., eds.). McGraw-Hill, New York]
  • Brystol Myers Squibb, that developed MTP inhibitors for the treatment of obesity, has recently decided to abandon this target, due to this fatty liver side effect.

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


Mercury

  • Liver enzyme levels, which are a proxy marker for liver dysfunction and non-alcoholic fatty liver disease (NAFLD)
    • Were found to be associated with mercury exposure in recent epidemiological studies

Metabolický syndrom

Přítomnost nejméně 3 abnormalit z následujících 5:

  • Obvod pasu u mužů více než 94 cm či 80 cm u žen
  • Hladina sérových triglyceridů více než 1,7 mmol/l
  • Hladina sérového HDL pod 1,0 mmol/l či u žen pod 1,3
  • Krevní tlak vyšší než 130 mmHg v systole či 85 mm Hg v diastole
  • Hladina glukózy nalačno vyšší než 5,6 mmol/l nebo přítomnost už rozvinutého DM 2. typu [2]

Methionine-choline-deficient (MCD) diet

  • U zvířat vyvolá
  • Can mimic histological and metabolic abnormalities of human disease
  • Induce either up- or downregulation of the expression of genes and proteins that are involved in
    • Lipid metabolism,
    • Inflammation,
    • Oxidative stress,
    • Fibrogenesis pathways
  • MCD diet model
    • Could spontaneously develop liver fibrosis within two to four weeks
    • Significant effects on the expression of genes that encode
      • proteins and enzymes involved in the liver fibrogenesis pathway
  • pubmed.ncbi.nlm.nih.gov/35164140/

Methotrexate


PNPLA3 genetic variant

  • Associated with steatosis, inflammation, fibrosis, cirrhosis
    • And even liver cancer.
  • 49 % of Hispanics in the study had the gene
  • 17% of African Americans
  • 23% of European Americans
  • Findings prompted researchers to explore drugs that target this variant
McCullough says

Paralen

  • NAFLD can increase the susceptibility to severe liver injury
    • With eventual acute liver failure induced by specific hepatotoxic drugs, including acetaminophen (APAP)

Several animal models

  • Predisposing role of hepatic steatosis to APAP intoxication
  • Association between NAFLD and APAP toxicity
    • PPAR
    • Coactivator peroxisome proliferator-activated receptor gamma coactivator 1-beta
    • Inflammation and mitochondria redox balance
  • Claim for a reduction of the maximal diurnal dose of APAP for subjects with liver steatosis.
  • pubmed.ncbi.nlm.nih.gov/32546444/


Perfluoroalkyl acids (PFAAs)

  • Induced liver steatosis
  • In the environment due to their extensive use in industrial and consumer products
  • Slow decay
  • Biochemical tests in rodent demonstrated
    • Potent modifiers of lipid metabolism
    • Cause hepatocellular steatosis
  • PFAAs interfere with mitochondrial beta-oxidation of fatty acids
    • Affect the transcriptional activity of peroxisome proliferator-activated receptor ? (PPAR?) in liver
  • Perfluorooctanoic acid (PFOA)
  • Perfluorononanoic acid (PFNA)
  • Perfluorohexane sulfonate (PFHxS)
  • Oral gavage for 7days to mice
  • Showed increased lipid accumulation in all treatment groups
  • Liver triglyceride (TG) levels were elevated in WT mice by all PFAAs
  • In vitro beta-oxidation of palmitoyl carnitine
    • By isolated rat liver mitochondria was not inhibited by any of the 7 PFAAs tested
  • PFAAs induce the expression of the lipid catabolism genes
    • As well as those involved in fatty acid and triglyceride synthesis, in WT mice
  • PFAAs increase liver TG load and promote steatosis in mice
    • Accumulation/synthesis and oxidation is disrupted to favor accumulation.
  • pubmed.ncbi.nlm.nih.gov/28049043/

Refeeding


Schistosomiasis

  • By flukes of the genus Schistosoma
  • Infect among others liver, intestine, bladder and urethra.
  • Trematodes can infect humans, i.e., S. haematobium, S. intercalatum, S. japonicum, S. mansoni and S. mekongi
  • Each year, 230–250 million persons are infected worldwide
  • Schistosomiasis is, therefore, the second most common parasitic infection after malaria (Nelwan 2019)

Specific rural Chinese population

  • People that previously have undergone schistosomal infection
    • Exhibit lower prevalence of diabetes
    • A better metabolic profile (Chen et al. 2013)

In vivo and in vitro experiments showed that S. japonicum infection

  • Leads to reprogramming of liver glycolipid metabolism
    • Decreased lipogenesis
    • Increased fatty acid catabolism (Xu et al. 2019)

Confirmed in HFD-fed, S. mansoni-infected mice

  • Showed an improvement of their metabolic syndrome features
  • However, these beneficial effects developed at the expense of more advanced liver injury
    • Suggesting the presence of both favorable as detrimental effects of schistosomal infection (da Silva Filomeno et al. 2020)
  • link.springer.com/article/10.1007/s00204-021-03069-1

Serotonin

  • Induced hepatic steatosis
  • Is associated with modulation of autophagy and notch signaling pathway
  • serotonin enhanced cancer cell proliferation/survival and drug resistance.
  • serotonin treatment
    • Up-regulated the expression of lipogenic proteins
    • Increased steatosis in liver cancer cells.
    • Enhanced cancer cell proliferation/survival and drug resistance

Inhibition of autophagy or Notch signaling

Serotonin receptor antagonists 5-HTr1B and 5-HTr2B

Selective serotonin reuptake inhibitors (SSRIs)


Steatohepatitis

Vinyl chloride, aflatoxin, trichloroethylene, tetrachloroethylene, trichloroethane, carbon tetrachloride, petrochemical mixtures, atrazine, paraquat, chlordecone, polychlorinated biphenyls, nitrobenzene, nitrotoluene, arsenic, methylmercury, thallium, yellow phosphorus, dioxin, lead, 2-nitropropane, N,N-dimethylformamide, chloroform

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Necrosis

Carbon tetrachloride and other halogenated aliphatic hydrocarbons, haloaromatic compounds, nitroaromatic compounds, arsenic, yellow phosphorus, acetaminophen

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Cholestasis

Beryllium, copper, di(2-ethylhexyl) phthalate, methylenedianiline, paraquat, toxic rapeseed oil

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Cirrhosis

Arsenic, carbon tetrachloride, polychlorinated biphenyls, trichloroethane, trichloroethylene, trinitrotoluene, vinyl chloride

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Peliosis hepatitis

Thorotrast, urethane, vinyl chloride

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Autoimmune hepatitis

Trichloroethylene, trinitrotoluene

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Granulomas

Beryllium, copper

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Pigment deposition

Anthracite, thorotrast, titanium

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Cholangiocarcinoma

Thorotrast, polychlorinated biphenyls

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Hepatocellular Carcinoma

Arsenic, carbon tetrachloride, polychlorinated biphenyls, tetrachloroethylene, thorotrast, trichloroethylene, trinitrotoluene, vinyl chloride

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Hemangiosarcoma

Vinyl chloride, butoxyethanol, chloronitrobenzene, polyhexamethylene biguanine, urethane, tetrafluoroethylene, thorotrast

Adapted from Cave, M., K. C. Falkner, and C. J. McClain, Occupational and Environmental Liver Disease. In Zakim and Boyer’s Hepatology: A Textbook of Liver Disease. 6th edn.

Chloroalkenes

  • Among the most commonly found contaminants at Superfund sites.

Tetrachloroethylene (PCE) and trichloroethylene (TCE)

  • Introduced as less hepatotoxic solvent alternatives to chloroalkane
  • High production volume chemicals have found widespread use as
    • Degreasers
    • Dry-cleaning fluids
  • Hepatotoxicity has been documented
  • TASH does appear to occur, particularly with PCE exposures
  • TCE hepatotoxicity more closely resembles autoimmune hepatitis

VC

  • Chemical intermediate
  • Exposures have been associated with TASH, HCC, and hemangiosarcoma
  • Mediator of occupational liver diseases, most notably hemangiosarcoma and TASH. VC is a high production volume chemical, and its worldwide capacity exceeds 35 million pounds. VC
is used for polyvinyl chloride (PVC) production and for thesynthesis of chlorinated solvents. To date, more than 80,000American chemical workers have been exposed to VC (Kielhorn et al. 2000). At production facilites such as Louisville,high-level exposures estimated to exceed 1,000 ppm occurredin ‘‘poly cleaners,’’ who entered and manually cleaned PVCbatch reactor vessels prior to 1975. VC exposures were subsequently limited by the Occupational Safety and Health Administration’s Vinyl Chloride Standard (29 CFR 1910.1017) to lessthan 1 ppm averaged over an 8-hr workday. In addition tochemical workers, high-level occupational exposures occurredin hair dressers, as VC was used as an aerosol propellant in hairspray from approximately 1962 through 1974 (Infante et al.2009). VC has been identified as a solvent degradation product,and it is present in landfill leachate where it potentially placessurrounding populations at risk.The identification of three cases of VC-related hemangiosarcoma at a single B.F. Goodrich chemical plant in Louisville,Kentucky, in the 1970s is perhaps the most important sentinelevent in occupational hepatology (Creech and Johnson 1974).In response to this outbreak, a liver cancer screening and surveillance program was instituted by the company in collaboration with the University of Louisville, and a large database andbiorepository was established (Dannaher, Tamburro, and Yam1981). Importantly, due to a long lag time, hemangiosarcomasstill occur in workers with high-level VC exposures prior toimplementation of the VC Standard (Figure 4). Elsewhere,studies have since documented associations between VC exposures and a variety of other liver pathologies including HCC(Mastrangelo et al. 2004), cirrhosis, peliosis hepatitis, focalhepatocytic hyperplasia (FHH), and focal mixed hyperplasia(FMH; Tamburro, Makk, and Popper 1984). VC is classifiedas a group 1 (definite) human carcinogen by the InternationalAgency for Research on Cancer (IARC).However, as early as 1975, it was recognized that ‘‘fattychanges’’ similar to those observed in ALD were present inabout half of biopsied chemical workers with high cumulativeexposures (Gedigk, Muller, and Bechtelsheimer 1975). In fact,in his final article addressing FHH and FMH, Hans Poppernoted that these lesions were often obscured by ‘‘fatty infiltration and/or chronic disease (hepatitis/granuloma)’’ (Tamburro,Makk, and Popper 1984). Our group became interested in thistopic following the publication of reports documenting steatohepatitis in lean Brazilian petrochemical workers exposed tochemical mixtures including VC (Cotrim et al. 2004) and ultrasound studies observing hepatomegaly, steatosis, and fibrosisin VC workers (Hsiao et al. 2004; Maroni et al. 2003). Subsequently, 25 liver biopsies from highly exposed VC workers atthe Louisville plant were reread, yielding an 80% steatohepatitis prevalence (Figure 5; Cave, Falkner, et al. 2010). Fibrosiswas present in 55% of TASH cases. Remarkably, serum transaminases were normal in most cases. TASH was associatedwith insulin resistance, reduced serum adiponectin levels,marked elevation of proinflammatory cytokines, reducedserum antioxidants, and necrotic, rather than apoptotic, hepatocellular death.It is perhaps not surprising that VC exposures result in steatohepatitis, because VC is metabolized in a strikingly similarfashion to ethanol. At concentrations up to approximately220 ppm, VC is metabolized by CYP2E1 forming the highlyreactive genotoxic epoxide, chloroethylene oxide. CYP2E1polymorphisms were associated with fibrosis, liver injury, andchromosomal damage in Asian VC workers and possiblyhemangiosarcoma at the Louisville plant (Antonino-Greenet al. 2000; Hsieh et al. 2007; Huang et al. 1997; Ji et al.2011). Chloroethylene oxide is either spontaneously or enzymatically converted into chloroacetaldehyde (CAA). CAA maybe metabolized by aldehyde dehydrogenase 2 or scavenged bysulfhydryl groups/GSH. Indeed, glutathione S-transferase(GST) polymorphisms have been associated with increasedbiomarkers of genotoxicity and liver disease in VC workers(Huang et al. 1997; Ji et al. 2011). Thus, VC is metabolizedin a similar fashion to ethanol and an exceptionally high prevalence of steatohepatitis occurred in highly exposed workers inassociation with insulin resistance, altered adipocytokines, andantioxidant depletion. VC-gene (CYP2E1, GST) interactionsappear to be important for hepatotoxicity. Because fatty liverhas been reported with occupational VC exposures at multiplesites, VC appears to be a model chemical for TASH.

TCE, a high production volume chemical and important

environmental contaminant, is a stable, colorless liquid at roomtemperature. Annual U.S. TCE production exceeds 300 millionpounds, primarily for use as a degreasing agent and chemicalintermediate; and an estimated 400,000 American workers areroutinely exposed. Common household products that containTCE include typewriter correction fluid, paint removers, adhesives, glues, and spot removers (ATSDR 1997b). Thus, homeindoor air contamination occurs. The largest source of environmental contamination stems from TCE evaporation from factories that utilize it for the removal of grease from metal. TCE isalso a groundwater contaminant, and it has been documented atover 1,500 hazardous waste sites and military installationswhere it was extensively used for degreasing aircraft and weapons (EPA 2009).Hepatotoxicity has long been documented following TCEexposures. HCCs occur in mice but not rats; and TCE is anIARC Group 2A (probable) human carcinogen. However, fatalhepatic necrosis with steatosis was documented following occupational TCE exposure as early as 1955. (Joron, Cameron,and Halpenny 1955). More recently, fatty liver accompanied byrash was reported in Chinese workers (Liu 2009); althoughother reports suggested that liver dysfunction more closelyresembled a hypersensitivity reaction or autoimmune hepatitis,rather than TASH (Cooper et al. 2009). Oxidative metabolitesof TCE include trichloroacetic acid (TCA) and to a lesserdegree, dichloroacetic acid (DCA). TCA is a ligand of the peroxisome proliferator–activated receptor alpha (PPARa), whichis involved in hepatic lipid metabolism. Fatty liver occurredwith TCE exposure in PPARa-null, and humanized PPARa(hPPARa) mice (Ramdhan et al. 2010) and rats (Kumar et al.2001). Similar to human reports, exposed guinea pigs developed fatty liver with dermal hypersensitivity (Tang et al. 2008).PCEPCE, also known as perchloroethylene (PCE), is a colorless,nonflammable liquid with a sweet smell. U.S. PCE demandexceeds 300 million pounds, largely for use as a chemical intermediate, dry cleaning fluid, and degreaser. It has been estimated that over 27,000 dry cleaners still use PCE, andground water contamination remains a significant concern. Ithas been shown that 1 to 3% of absorbed PCE metabolizes intoTCA and is sequentially eliminated in the urine. The remaining97 to 99% is exhaled as PCE (ATSDR 1997a).PCE exposures have been associated with liver disease inhuman and animal studies. TASH was noted in a study of 29dry cleaner workers exposed to PCE at 16 ppm (Brodkinet al. 1995). A greater percentage of hepatic parenchymalchanges, including fatty infiltration, were noted in dry cleaningoperators than in nonexposed laundry workers (67% vs. 39%).Most PCE-exposed workers with fatty liver had normal serumaminotransferases. More recently, fatty liver by magnetic resonance imaging (MRI) was reported in an elderly woman withdaily PCE exposures who worked in the dry cleaning industry(Pezzini et al. 2008). The majority of animal studies focus onHCC, and PCE is a probable human carcinogen (Lash and Parker 2001). Indeed, a significantly elevated risk for primary livercancer was demonstrated in female launderers and dry cleaners(Lynge and Thygesen 1990). However, fatty liver was noted inmice following acute PCE inhalation exposures as early as1962 (Kylin et al. 1962). Notably, PCE produced a similardegree of steatosis as chloroform but significantly more steatosis than TCE. Hepatic steatosis was more recently noted inmice treated with high-dose PCE (Philip et al. 2007).ChloroalkanesChlorinated alkanes, including chloroform, carbon tetrachloride, dichloroethane, trichloroethane, and tetrachloroethane, have been used as industrial solvents, chemicalintermediates, and medicine (anesthetic agents) since the1850s. However, exposure to these compounds has been associated with steatohepatitis and acute liver failure. With theadoption of less hepatotoxic anesthetic agents, reports of acutechloroalkane intoxication have also dwindled, and now casestudies of acute intoxication with chlorinated alkanes tend todescribe workplace accidents and incidents of drug abuse (Choiet al. 2006; Kim 2008; Lionte 2010). The demonstrated toxicityof chloroalkanes coupled with their ozone-depleting effects hasresulted in strong efforts to replace them with less toxic alternatives. However, low-level chronic occupational exposureshave led to some reports of clinical liver injury that may hintat a much larger subclinical population (Halevy et al. 1980).Chlorinated aliphatic compounds remain in use in industry asdegreasers because of their superior properties as solvents oforganic molecules and are particularly common in the drycleaning industry. Occupational exposure is typically by inhalation or skin absorption. Most absorbed trichloroethane isexcreted in exhaled breath or biotransformed via CYP2E1 totrichloroethanol or TCA and excreted in urine.ChloroformChloroform was one of the first anesthetic agents to be usedin surgery, and its use continued into the second half of thetwentieth century, despite a strong history of hepatotoxicity.Chloroform is a classic liver toxicant, causing steatosis withmid-zonal (zone 2) or centrilobular (zone 3) necrosis (Thorpeand Spence 1997). Although no longer in use as an anestheticagent, chloroform is a by-product of water chlorination, andhumans are exposed to it in drinking water, or breathing vaporthat has been volatilized by hot water in the shower. However,the potential impact of chronic low-level environmentalchloroform exposures on fatty liver disease is unknown.Carbon TetrachlorideCarbon tetrachloride (CCl4) was in widespread use as a solvent, vermicide (kills worms), refrigerant, and in fire extinguishers. However, its use for these applications was limitedafter several hundred cases of its toxicity were reported in theearly to mid-twentieth century (Zimmerman 1999). It has continued to be used as a feedstock for the synthesis for chlorofluorocarbon (CFC) gases. However, following the adoptionof the Clean Air Act and the Montreal Protocol banning CFCs,U.S. carbon tetrachloride production has been reduced to 130million pounds per year (ATSDR 2005). CCl4 is a stable molecule and a persistent environmental pollutant but does notappear to bioconcentrate in animals. Nonetheless, CCl4 is aubiquitous ambient air pollutant and may also contaminategroundwater supplies. The estimated daily intake by the U.S.general population from air and water ranges from 12 to 511mg/day and from 0.2 to 60 mg/day, respectively.The primary route of acute carbon tetrachloride poisoning isvia inhalation, leading to multiorgan failure and death in 25% ofthe cases (Zimmerman 1999). A prodromal phase consisting ofdizziness, headache, confusion, nausea, vomiting, and diarrheasubsided for 1 to 2 days before the onset of acute liver failure,typically including extremely high transaminase levels. TheAST levels were usually greater than ALT levels, and in onecase it reached 27,000 U/L. Jaundice developed in half of thecases. Hepatic coma and ascites developed in severe cases.350 WAHLANG ET AL. TOXICOLOGIC PATHOLOGYOliguric renal failure ensued and was the usual cause of death, asmost cases occurred before the advent of hemodialyisis. Whendeath occurred, it was typically within 10 days of exposure.Liver histopathology consisted of centrilobular (zone 3) steatosis and necrosis was also observed in the renal tubular epithelium in most fatal cases. Similar to acetaminophen overdose,recovery was typically rapid in those who survived. Treatmentwas supportive, although some reports attributed benefit tointravenous N-acetylcysteine or hyperbaric oxygen (Zimmerman 1999). Cirrhosis has been reported in cases of chronic exposure (ATSDR 2005).Although human cases of acute carbon tetrachloridepoisoning seldom occur today, it remains the classic experimental model of occupational hepatotoxicity. Carbon tetrachloride is a well-studied hepatotoxicant, which has beenshown multiple times to induce liver injury (steatosis, necrosis,fibrosis, and HCC) similar to that observed in humans. As withother chlorinated aliphatic compounds, bioactivation of CCl4by CYP2E1 to reactive metabolites is critical for its toxicity(Manibusan, Odin, and Eastmond 2007). The mechanisms ofacute CCl4 hepatotoxicity involve immediate cleavage of CCl4by CYP2E1 in hepatocytes (Johansson and IngelmannSundberg 1985), which generates the trichloromethyl radical,leading to lipid peroxidation and membrane damage (Recknagel et al. 1989). Subsequently, activated hepatic macrophages(Kupffer cells) produce toxic mediators (e.g., inflammatorycytokines, reactive oxygen intermediates, and eicosanoids),resulting in the injury of parenchymal cells (Edwards et al.1993).It was shown that chronic alcoholics had increased susceptibility to CCl4 poisoning (Zimmerman 1999). It is well knownthat CYP2E1 is robustly induced by alcohol and can contributeto a far greater amount of total alcohol metabolism in alcoholdependent individuals (Beier and McClain 2010; Lieber 1997).Therefore, the induction of this enzyme by chronic abuse ofethanol may increase the risk of liver damage by other agents(e.g., CCl4). More recently, higher hepatic CYP2E1 expressionand activity have also been associated with obesity and NAFLD(Aubert et al. 2011). Acute CCl4 also enhanced liver damage inmice fed the obesogenic Western diet (Allman, Gaskin, and Rivera 2010). Therefore, although it has not been directly studied inhumans, it is distinctly possible that obesity and related sequelae(e.g., NAFLD) will also increase the susceptibility to CCl4.Chloroethanes1,1,1-trichloroethane was considered to be the least hepatotoxic halogenated hydrocarbon solvent available based on studies undertaken in the late 1950s and 1960s (Hodgson et al.1989). Consequently, it was widely used as an industrial solvent and was present in many household cleaners and adhesivesuntil its use was phased out due to ozone depletion. Fatalitiesassociated with exposure to 1,1,1-trichloroethane are generallyrelated to abuse, and like 1,1,2-trichloroethane, are most oftendue to its central nervous system (CNS) depressant effects.Hepatic effects have been described as transient (Halevyet al. 1980).In contrast, 1,1,2-trichloroethane is a relatively potent hepatotoxin and its industrial use is therefore restricted. There are afew reports of adverse effects from occupational exposures, butanimal experiments have suggested the potential for steatohepatitis as well as HCC (NIOSH 1978). A mouse study (90-day)demonstrated liver enzyme elevation with GSH depletion following 1,1,2-trichloroethane exposure in drinking water(White et al. 1985).1,2-dichloroethane has been shown to cause elevations inALT in mice associated with hepatomegaly and steatosis(Storer, Jackson, and Conolly 1984). In humans, acute toxicitycaused elevated liver enzymes, hepatomegaly, and centrilobular (zone 3) necrosis (ATSDR 2001). The hepatotoxic effects of1,1-dichloroethane are considerably milder than those of 1,2-dichloroethane, possibly due to the differences in metabolismand the generation of toxic intermediates (Mitoma et al.1985; Wilbur and McClure 2004).Volatile Organic CompoundsVolatile organic compounds (VOCs) such as benzene,toluene, styrene, and xylene are colorless, flammable liquidswith a sweet odor that evaporate quickly into air. VOCs maybe used as solvents or chemical intermediates. Reported U.S.production for benzene was 2.775 billion gallons in 2008(Kirschner 2009), toluene with 1.905 million gallons in 2005(Kirschner 2006), and styrene with 9.605 million pounds peryear (Kirschner 2004).Petrochemical workers, painters, and printers are frequentlyexposed to VOC mixtures. VOC exposures have been associated with TASH with both normal liver enzymes (Brautbar andWilliams 2002; Cave, Falkner, and McClain 2011) and abnormal liver enzymes (Cotrim et al. 1999). Several studies document steatohepatitis by pathology or ultrasound in exposedpetrochemical workers, painters, or printers with abnormalliver enzymes. A study from Brazil showed that 20 nonobese,nondrinking petrochemical workers with abnormal liverenzymes had hepatic steatosis on biopsy following exposureto 18 industrial chemicals including benzene, toluene, xylene,styrene, and VC. Repeat liver biopsies 8 to 14 mo followingremoval from the workplace showed improvement in the severity of steatosis in 9 of the 10 subjects (Cotrim et al. 1999). Steatohepatitis was confirmed in subsequent reports of Brazilianpetrochemical workers (Barberino et al. 2005; Cotrim et al.2004). Likewise, at a petrochemical plant in Argentina, 27 of92 workers exposed to VOCs had elevated transaminase levels.Fatty liver was subsequently detected by ultrasound in 14 of thesubjects with aminotransferase elevation (Perez et al. 2006).Eleven of 13 household painters with VOC exposures andabnormal liver enzymes had fatty liver on biopsy (Dossinget al. 1983). Likewise, all 8 toluene-exposed printers with persistent mild liver enzyme elevation had hepatic steatosis(Guzelian, Mills, and Fallon 1988).Vol. 41, No. 2, 2013 TOXICANT-ASSOCIATED STEATOHEPATITIS 351Several additional serum biomarker studies have been performed to evaluate VOC hepatotoxicity and/or TASH.Although pathology was not provided, based on the aforementioned liver biopsy and ultrasound studies, we suspect that asignificant proportion of subjects with elevated hepatotoxicitybiomarkers had TASH. For example, a 45.55% prevalence ofliver enzyme elevation occurred in shoe repairmen exposedto toluene (Tomei et al. 1999). Serum bile acids have been proposed as an alternate biomarker for solvent hepatotoxicity andwere elevated in toluene- and xylene-exposed workers (Francoet al. 1986) as well as workers exposed to styrene when processing sewage pipes (Edling and Tagesson 1984). An increasein g-glutamyltransferase was associated with exposure to amixture of 6 VOCs including benzene, toluene, and xylene (Liuet al. 2009) in the National Health and Nutrition ExaminationSurvey (NHANES). Our group reported elevated adipocytokines in elastomer workers exposed to styrene, butadiene, andacrylonitrile mixtures in conjunction with elevated serum cytokeratin 18 consistent with TASH (Cave, Falkner, and McClain2011).Dioxins and PCBsDioxins and PCBs are structurally similar polychlorinatedaromatic POPs. Dioxins and some PCBs bind and activate thearyl hydrocarbon receptor (AhR). Although tumors and a wasting syndrome are the most classically described toxicologiceffects of these chemicals, more recent data suggest that TASHmay also occur.DioxinsPolychlorinated dibenzo-para-dioxins (PCDDs), popularlyknown as dioxins, are persistent environmental contaminantsand unwanted by-products of industrial processes such asincineration, metal processing, and pesticide production. Dioxins contain two benzene rings connected by two oxygen atomsand contain four to eight chlorines with a total of up to 75 congeners. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the mostpotent congener of the series, was a contaminant of AgentOrange, a defoliant used during the Vietnam War. TCDD wasclassified by the IARC as a Group 1 carcinogen in 1997 (IARC1997). Dioxins are found in air, sediments, and soil. Mosthuman exposures to dioxins occur through food consumptionsuch as poultry, milk, fish, and meat since these persistent compounds accumulate in animal fat. Occupational exposures todioxins, particularly TCDD, have been reported since the1940s with the Seveso disaster, an industrial explosion in Italyin 1976, contributing to the highest known exposures to TCDD(Sweeney and Mocarelli 2000). Another poisoning episodeoccurred in 1977 in Missouri, where salvage oil was contaminated with TCDD, due to improper disposal of industrial toxicwaste (Kimbrough et al. 1977). Dioxin levels in humans havedecreased over time.In addition to tumor development and a wasting syndrome,hepatotoxicity is a major defining feature of TCDD toxicity inlaboratory animals as seen in rat, mouse, chicken, zebra fish,guinea pig, and rabbit, which was the most sensitive speciesto liver toxicity (El-Sabeawy, Enan, and Lasley 2001; Mann1997; Zodrow, Stegeman, and Tanguay 2004). Apart fromhepatocellular tumors, other toxic manifestations in the liverwere steatosis, hepatic necrosis, inflammation, multinucleatehepatocytes, and cytoplasmic vacuolation. TCDD administration in immature, ovariectomized C57B/l/6 mice either aloneor in combination with another environmental pollutant, PCB153, resulted in hepatic histological changes including lipidaccumulation, hepatocellular hypertrophy inflammatory cellinfiltration, hyperplasia, and necrosis (Kopec et al. 2011).Notably, another study demonstrated an increase in total hepatic fatty acids and triglycerides and serum ALT levels inTCDD-treated mice (Boverhof et al. 2006). A recent studyshowed that TCDD increased fatty acid transport by utilizingdietary fat rather than carbohydrate sources to elicit fatty liverdisease (Angrish et al. 2012).In contrast to animal studies, it is unclear whether TASHoccurs in TCDD-exposed humans. Nonetheless, some humanstudies demonstrate alteration in liver enzymes in both adultsand children following TCDD exposures. A follow-up studyon an Austrian cohort of chemical workers involved in herbicide production suggested that high TCDD exposure at ayounger age led to chronic liver disease (Neuberger et al.1999). Clinical chemistry on TCDD-exposed subjects showedelevated g-glutamyl transferase (g-GT), AST, and ALT levelsas compared to controls. Some subjects exhibited weight losswith increased TCDD plasma concentrations while in othersubjects; weight gain was reported as TCDD plasma concentrations decreased. A trend for an increase in chronic liver diseasewas also reported in another long-term follow-up study with aTCDD-exposed subcohort (Zober et al. 1994).Dioxins exert their effects by high-affinity binding to theAhR, an intracellular ligand-activated receptor that belongsto the PAS domain protein family of transcription factors(Denison et al. 2002). Although more traditionally linked tohepatocarcinogenesis, AhR activation by TCDD has morerecently been shown to cause hepatic steatosis in rodents. AhRactivation interferes with peripheral fat mobilization, increasesfatty acid uptake in the liver by upregulating CD36 and otherfatty acid transporters, and suppresses peroxisomal b-oxidationof fatty acids leading to hepatic triglyceride accumulation (Leeet al. 2010). TCDD also induces hepatic dyslipidemia by AhRmediated induction of stearoyl-CoA desaturase 1, the enzymethat catalyzes the rate-limiting step in monounsaturated fattyacid biosynthesis and hence alters hepatic lipid composition(Angrish et al. 2012). However, the effects of AhR on lipidhomeostasis in humans must be investigated further due tospecies-specific differences in gene batteries activated by AhR.PCBsPCBs are halogenated compounds consisting of up to 10chlorine atoms attached to a biphenyl group. They were manufactured during 1930s to 1970s and were used as dielectric andheat transfer fluids in electric capacitors, wax extenders, and352 WAHLANG ET AL. TOXICOLOGIC PATHOLOGYflame retardants. A total of 1.3 million tons of PCB mixturescontaining 130 congeners were manufactured worldwide priorto 1977 (Breivik et al. 2002). Although PCB production wassubsequently banned by the Stockholm Convention, their highthermodynamic stability makes PCBs resistant to environmental degradation, and thus, they are POPs. PCBs are present inthe ecosystem, including the atmospheric air, lakes, rivers, fish,human adipose tissue, and serum, and breast milk. PCBs stillcontaminate the food supply, and daily intake in the Americandiet is estimated to be approximately 30 ng/day based on arecent study from a Dallas supermarket (Schecter et al. 2010).Acute effects due to PCB toxicity such as fatigue, anorexia,nausea, and jaundice were known since the 1930s (Flinn andJarvik 1938), although evidence of cancer due to occupationalexposures to PCBs was not observed in chemical workers untilthe 1960s. The ‘‘Yusho disease’’ that occurred in Japan in 1968due to contamination of edible rice oil with a PCB mixtureclearly pointed out the carcinogenic effects of PCBs. A mortality report on the Yusho patients showed an increased risk for allmalignancies upon PCB exposure with an elevated risk for primary liver cancer (Kuratsune et al. 1987). Subsequent cohortstudies of exposed electrical capacitor workers also demonstrated increased hepatobiliary malignancy rates; and PCBs areIARC Group 2A carcinogens. Occupational PCB exposure wasassociated with elevated liver enzymes and hepatomegaly(Maroni et al. 1981). We became interested in PCBs after ourexposome-wide study demonstrated that 20 congeners weredose-dependently associated with suspected fatty liver diseasein adult NHANES participants (Cave, Appana, et al. 2010). Insubjects involved in the ‘‘Yu-cheng’’ incident in Taiwan wherecooking oil had been highly contaminated by PCBs, the mortality rate due to cirrhosis was 2.7-fold higher than expected (Yuet al. 1997).In contrast to human studies, pathologic data documenthepatic steatosis following PCB treatment in animal studies.Long-term rat studies conducted by the National ToxicologyProgram document ‘‘toxic hepatopathy’’ which is characterizedby prominent steatosis, inflammation, and fibrosis and could beconsidered to represent a TASH variant (NTP 2006). Moreover, we recently demonstrated that PCB 153 exposure causesTASH with hepatic antioxidant depletion (Shi et al. 2012).PCB mode of action in TASH is uncertain but appears to becongener specific and critically dependent on nutrient interactions, at least in mice (Hennig et al. 2005; Shi et al. 2012).Coplanar, or dioxin-like PCBs, bind and activate the AhR andare expected to have similar modes of action to dioxin. In contrast, some non-coplanar PCBs may activate the pregnane xreceptor (PXR) or the constitutive androstane receptor (CAR)in a tissue- and substituent-dependent manner (Al-Salman andPlant 2012). However, the potential importance of the activation of these receptors in PCB-mediated TASH is unknownPesticidesPesticides are compounds or mixtures intended to kill, inactivate, repel, or mitigate pests and are primarily used foragricultural and antimalarial purposes. According to the Stockholm Convention on Persistent Environmental Pollutants in2001, 9 of the 12 most harmful chemicals, the so-called ‘‘dirtydozen,’’ were pesticides. Pesticides are not limited to commercial use and 74% of U.S. households use pesticides. Pesticidesare associated with over 3 million acute poisonings and250,000 deaths per year. In 2007, the world expenditure on pesticides was $39.4 billion, with the U.S. expenditure alone totaling $12.5 billion (Grube et al. 2011). Limited data suggest thatsome pesticides including organochlorine insecticides and triazine herbicides may be associated with TASH.Organochlorine InsecticidesOrganochlorine insecticides include but are not limited todichlorodiphenyltrichloroethane (DDT); cyclodienes, namelychlordane, dieldrin, aldrin, endrin, and heptachlor; and cagedstructures such as mirex and chlordecone. DDT is the mostabundant parent compound of its class. DDT was marketedas an insecticide beginning in 1944, and a total of 1.8 milliontonnes have been produced globally since then. Organochlorinepesticides have been banned from most agricultural use forover three decades, after adverse effects on wildlife wereobserved. However, organochlorine insecticides are thermodynamically stable POPs that continue to contaminate livingorganisms and the human food supply. Although DDT is aknown carcinogen in rodents, occupational human exposureshave only been occasionally linked to liver cancer, among others. Thus, DDT is an IARC Class 2B (possible) humancarcinogen.Hepatic effects, including steatosis, were reported in achlordecone intoxication incident involving 32 plant workersin Virginia (Guzelian et al. 1980). Many of the cases had hepatomegaly, and 12 workers underwent liver biopsy, revealingmild steatosis, portal inflammation, fibrosis, glycogenatednuclei, and lipofuscin accumulation. Interestingly, liverenzymes were repeatedly normal in all subjects, a characteristiccommonly observed in TASH. Chlordecone undergoes enterohepatic circulation and cholestyramine was successfully usedto promote chlordecone elimination. Using the NHANES2003–2004 database, we investigated the effects of chronic,low-level exposures to organochlorine insecticides on liverenzymes in American adults (Patel et al. 2009). We reportedmultiple pesticides including dieldrin, trans-nonachlor (component of chlordane), and heptachlor epoxide (metabolite) thatwere dose dependently associated with increased odds ratiosfor ALT elevation and suspected NAFLD. The hepatotoxicmodes of action for organochlorine insecticides are unknown,but they are known to induce cytohrome P450 enzymes andappear to activate nuclear receptors. More data are needed todetermine whether TASH is a significant problem resultingfrom exposures to these legacy POPs.Triazine HerbicidesHerbicides are widely used in the U.S. agricultural sector,accounting for about 70% of total pesticide usage. The triazineVol. 41, No. 2, 2013 TOXICANT-ASSOCIATED STEATOHEPATITIS 353family of herbicides, including atrazine and simazine, werefirst introduced in the 1950s. Triazine herbicides were bannedin the European Union, but widespread use continues in theUnited States. Triazines may contaminate groundwater, particularly in the summer months following application. Liver steatosis was reported in B6C3F1 mice fed with simazine for 35weeks. Hepatic triglycerides increased and mitochondrial oxidative phosphorylation was perturbed after long-term simazinefeeding in these mice (Vancova et al. 2000). Simazine toxicosisin sheep also revealed fatty liver change in these animals(Allender and Glastonbury 1992). Chronic exposure to atrazineled to steatosis, obesity, insulin resistance, and mitochondrialdysfunction in Sprague-Dawley rats (Lim et al. 2009). Triazineherbicides mediate their actions by inhibiting the electrontransport chain in chloroplasts and hence are photosynthesisinhibitors. The similarity between plant chloroplasts and mammalian mitochondria may be responsible for the mitochondrialtoxicity induced by triazine exposures in animal studies. However, there are currently insufficient data to correlate triazinehuman exposures to TASH.Nitroaliphatic Chemicals2-Nitropropane, a high production volume chemical, hasbeen used in numerous applications since 1940, includingprinting inks and dyes, adhesives, resins, waxes, waterproofcoatings, varnish remover, and as a fuel additive (Harrison,Letz, et al. 1987; Zimmerman 1999). 2-nitropropane stands outas the most toxic of the nitroaliphatic compounds, leading tosevere hepatic injury in humans including fatty change, centrilobular (zone 3) necrosis, bile duct proliferation with accompanying cholestasis, fulminant hepatic failure, and death(Harrison, Letz, et al. 1987; Farrell 1994). In experimental animals, hepatotoxic effects are species dependent but generallyinclude steatosis, necrosis, and liver tumors (Zitting, Savolainen, et al. 1981). Proposed mechanisms include oxidativestress and lipid peroxidation via catalase inhibition and mitochondrial dysfunction.N-Substituted Amide SolventsN,N-Dimethylformamide (DMF) is a solvent commonlyused in the synthetic leather and polyurethane industry and hasbeen implicated in case reports of hepatic injury, includingsteatohepatitis, fibrosis, cirrhosis, and cancer (Nakasone et al.2011; Nomiyama et al. 2001; Redlich et al. 1988). In a 1990polyurethane worker study, workers exposed to DMF for lessthan 3 months showed marked elevations in AST and ALT,with the ratio of ALT/AST always greater than 1, indicativeof nonalcoholic liver injury. Workers exposed for longer than1 year showed much more modest elevations in liver enzymes.On biopsy, microvesicular and/or macrovesicular steatosis wasapparent in short-term exposed workers, along with enlargedKupffer cells in zones 1 and 2 and evidence of hepatocyteinjury. Steatosis persisted over time and progressed to moderate and/or severe fatty change. Hepatocytes in these workerswere notable for prominent smooth endoplasmic reticulum,small fat droplets, and pleomorphic mitochondria (Redlichet al. 1990). Dimethylacetamide (DMAC), a related solventused in the manufacture of synthetic fibers and acrylic resins,has also been investigated as a cause of occupationalexposure-related liver injury. Experiments with dogs showedfatty change after dermal application for 6 weeks (Kim1988). Thus, exposures to N-substituted amide solvents appearto be associated with TASH.MetalsMetals including arsenic, mercury, and lead are potentiallyassociated with TASH. While arsenic is a classically describedhepatotoxicant, the liver is not traditionally considered to be aprincipal target organ for lead and mercury toxicities, despitethe fact that these metals concentrate within the liver. However,limited data suggest that steatosis occurs following exposure tothese metals, and more research is needed to determine the significance of these findings to human populations.ArsenicInorganic arsenic is a ubiquitous element and a drinkingwater contaminant. Owing to its toxic potential to humans,Arsenic is a high-priority hazardous substance in the UnitedStates. Chronic exposure to arsenic has been linked with a myriad of possible health effects, including skin lesions, hypertension, cardiovascular disease, respiratory disease, andmalignancies of the skin and internal organs (Waalkes et al.2004). The liver is a well-known target organ of arsenic exposure. Hepatic abnormalities caused by arsenic exposure includehepatomegaly, noncirrhotic portal fibrosis, portal hypertension,HCC, and hemangiosarcoma (Mazumder 2005; Santra et al.1999, 2000; Smith et al. 1992; Waalkes et al. 2006).The major route of arsenic exposure is via ingestion of wellwater. High levels of arsenic can be found naturally in somewater sources such as in West Bengal, an area with an unexpectedly high level of NAFLD in nonobese individuals, or asa consequence of mining activity where arsenic frequently contaminates mine tailings and then leaches into the water supply(Das et al. 2010). The hepatotoxic action of arsenicals is oftenattributed to the ability of either arsenite or its metabolites toinduce oxidative stress. Arsenite binds lipoic acid in the mitochondria leading to inhibition of pyruvate dehydrogenase withresultant mitochondrial uncoupling and an increase in hydrogen peroxide production (Patrick 2003). Increases in free radical production, lipid peroxidation products, and oxidized DNAdamage have been reported in multiple studies.Although arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than that present inthe U.S. water supply. However, the risk for developing ahuman disease derived from environmental exposure is notbased solely on that environmental exposure but is rather modified by other mitigating conditions, such as genetic (e.g., polymorphisms in key genes) or other environmental (e.g., diet,lifestyle, etc.) factors. Indeed, it was recently shown thatarsenic exposure, at concentrations that are not overtly354 WAHLANG ET AL. TOXICOLOGIC PATHOLOGYhepatotoxic, enhances LPS-induced liver injury in mice (Arteelet al. 2008). Straub et al. (2007) demonstrated that mouse liveris also sensitive to more subtle hepatic changes (e.g., hepaticendothelial cell capillarization and vessel remodeling) at lowerarsenic exposure levels (250 ppb) without any gross pathologiceffects. It is nevertheless unclear at this time whether environmental arsenic exposure at the levels observed in the UnitedStates causes fatty liver disease. However, a striking featureof arsenic exposure and NAFLD is the significant overlapbetween areas of risk in the United States (Mokdad et al.2003; Welch et al. 2000). For example, states with clusters ofmunicipal wells with high levels of arsenic (e.g., Michigan,Texas, West Virginia, and Oklahoma; U.S. Geological Survey2007) also have high incidences of obesity and diabetes.Furthermore, high arsenic in the drinking water is generallylocalized to private artesian water supplies (not regulated bythe Environmental Protection Agency [EPA]) in rural communities, where the incidence of obesity tends to be even higherthan in most areas of the country (National Center for Health2001). It is therefore possible that arsenic exposure is an unidentified environmental risk factor in the development ofNAFLD. In support of this hypothesis, it was recently demonstrated that liver injury during experimental NAFLD isenhanced by concomitant arsenic exposure in mice (Tanet al. 2011), suggesting that the relative risk of hepatic damagecaused by arsenic exposure may have to be modified to takeinto account other mitigating factors, such as underlyingNAFLD.Mercury and LeadThe liver is not traditionally considered to be a target organfor mercury and lead toxicities. However, mercury and leadexposures were dose dependently associated with suspectedNAFLD in NHANES participants (Cave, Appana, et al.2010). Case studies and anecdotal reports involving fulminanthepatic failure or hepatitis following mercury exposure havebeen reported (Al-Sinani, Al-Rawas, and Dhawan, 2011; Wiwnaitkit and Chaiyasit 2011). Previous human epidemiologicalstudies have inconsistently linked mercury contamination inJapanese fishing villages to increased liver-related mortalityin villagers (Futatsuka et al. 1992; Futatsuka et al. 2005; Futatsuka, Shibata, and Kinjo 1987).Despite the fact that methyl mercury (MeHg) concentratesconsiderably within the liver due to enterohepatic recirculation,few animal studies have examined the potential role of MeHgin liver disease. However, acute and chronic toxicity studiesconducted in rats and cats demonstrated that mercury exposureresulted in depletion of body fat with development of centrilobular (zone 3) hepatic steatosis with increased lipid peroxidationproducts, proliferation of the endoplasmic reticulum, and floccular degeneration of the mitochondria with extrusion of diseased organelles into the sinusoidal space (Chang andYamaguchi 1974; Desnoyers and Chang 1975; Klein et al.1972; Lin, Huang, and Huang 1996). Many of these changeswere irreversible even after discontinuation of MeHg exposure.The primary mechanism of MeHg hepatotoxicity may berelated to its high affinity for sulfhydryl residues and consequent poisoning of cysteine-containing proteins and GSHdepletion (Lin, Huang, and Huang 1996).Most clinical cases of lead intoxication are related to its neurological effects. Although hepatotoxicity has been reported inanimal studies, there are only a few case studies in humansdescribing reversible microvesicular and macrovesicular steatosis, and hepatitis (Beattie et al. 1979; Verheij et al. 2009).Although ‘‘lead-induced hepatic hyperplasia’’ is a classicpathologic liver lesion, a recent mouse study of inhaled leadacetate documented centrilobular (zone 3) hepatic steatosis,hepatocyte proliferation, apoptosis, inflammatory infiltrate,and fibrosis (Rendon et al. 2012). More work is required to document the potential role and mechanisms of arsenic, lead, andmercury in TASH.

total parenteral nutrition (ie, intestinal failure-associated liver disease [IFALD]) and immune checkpoint inhibitors (ICIs). The hallmark features of IFALD are cholestasis and steatosis. Cholestasis is more common in infants, whereas steatosis and steatohepatitis are more commonly seen in older children and adults. Infants tend to have a faster progression to fibrosis and cirrhosis. Perivenular fibrosis and ductopenia may also be seen in IFALD. Although fish oil-based lipid emulsions can reverse cholestasis, recent studies have shown persistent or progressive fibrosis. ICI-induced liver injury usually presents as an acute hepatitis with features similar to those seen in idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. However, it lacks a prominent plasma cell infiltrate and serological markers of autoimmune hepatitis. Other features such as fibrin ring granulomas and cholangitis have also been reported in association with ICIs. Treatment for ICI-induced liver injury includes corticosteroids and other immunosuppressants.https://pubmed.ncbi.nlm.nih.gov/31669893/

Bisfenol A


Cannabinoids

  • Acting primarily via CB1 and CB2 receptors
  • Receptors in normal liver is low or absent
  • Up-regulation of the expression of CB1 and CB2 receptors in
    • Hepatic myofibroblasts
    • Vascular endothelial cells,
    • Increased concentration of endocannabinoids in liver in the course of chronic progressive liver diseases

CB1 receptor signalling :-(

  • Profibrogenic and proinflammatory effects in liver tissue
  • Primarily due to the stimulation of hepatic stellate cells
  • Progression of liver steatosis

CB2 activation signalling :-)

    • Inhibits or even reverses liver fibrogenesis

End-stage liver disease

  • Endocannabinoid system
    • Contribute to hepatic encephalopathy and vascular effects
    • Portal hypertension,
    • Splanchnic vasodilatation,
    • Relative peripheral hypotension
    • Probably cirrhotic cardiomyopathy
  • Available evidence is based on cellular cultures or animal models.
  • Clinical data on the effects of cannabinoids in chronic liver diseases are limited. However,
  • Recent studies have shown the contribution of cannabis smoking to the progression of liver fibrosis and steatosis.
  • pubmed.ncbi.nlm.nih.gov/18985799/


Chlamydia pneumoniae (C. pneumoniae)

  • A respiratory pathogen

Small study with male patients

  • C. pneumoniae IgA seropositivity was significantly more often present in patients suffering from NASH (53.3 vs 5%)
  • While this was not the case for IgG (Bolukbas et al. 2005)
  • Correlation might reflect earlier studies that report a link between
    • Persistent C. pneumoniae infection and the metabolic syndrome (Laurila et al. 1997; Leinonen and Saikku 1999)

C. pneumoniae infection induced dyslipidemic effects in mice

  • Altered the hepatic expression of genes involved in lipid metabolism
  • Reduced expression of CPT1A and acyl-CoA dehydrogenase medium chain (ACADM)
  • Expression of liver IL1B mRNA was induced (Marangoni et al. 2015)
    • Indicating an inflammatory response
  • link.springer.com/article/10.1007/s00204-021-03069-1

Chlamydia trachomatis (C. trachomatis)

  • Prevalent sexually transmitted organisms
  • Obligate intracellular Gram-negative bacteria (Di Pietro et al. 2019)
  • Intervene with hepatic lipid metabolism and inflammation

In Chang Liver cells

  • C. trachomatis induced fatty acid uptake
    • Via fatty acid binding protein 1 (L-FABP) expression
      • Promoted chlamydial intracellular growth (Wang et al. 2007)

C. trachomatis-infected mice

  • Showed increased hepatic IL-6 and TNFA mRNA expression
    • Both are typical markers involved in NASH
  • Accompanied with decreased levels of the
    • De novo lipogenic genes acetyl-coenzyme A carboxylase (ACC)
    • FAS (Marangoni et al. 2015).
  • link.springer.com/article/10.1007/s00204-021-03069-1


Dietary risks included

Low intake

  • Fruits, vegetables,
  • Legumes,
  • Whole grains,
  • Nuts/seeds,
  • Milk,
  • Fiber,
  • calcium,
  • Seafood omega-3 fatty acids,
  • Polyunsaturated fatty acids

High intake

  • Red meat, processed meat,
  • sugar-sweetened beverages,
  • Trans fatty acids,
  • Sodium

Metabolic risks

  • High low-density lipoprotein cholesterol,
  • Systolic blood pressure (BP),
  • Fasting glucose (FG),
  • Body mass index (BMI),
  • Low bone mineral density
  • Impaired kidney function (IKF)
PMID: 34558838 PMCID: PMC8710798 DOI: 10.1002/hep4.1707


Endotoxins from GIT by fructose

Studies in mice

  • Fructose in the small intestine is related to the development of endotoxemia
  • Increasing gut-derived bacteria elements such as
    • Lipopolysaccharides
    • Unmethylated DNA
  • Such bacterial products are ligands of endogenous Toll-like receptor 4 (TLR4)
    • Triggering inflammation responses involved in NAFLD, NASH and liver fibrosis.
  • TLR4 may mediate the deleterious effects of dietary fructose on NAFLD
    • Demonstrated using TLR4-deficient mice

Controlled studies involving either fructose or glucose challenges in adolescents

  • Under both acute and chronic schemes
  • Higher postprandial endotoxin levels after fructose consumption compared to glucose
  • Reductions in sugars consumption are often accompanied by
    • Increased intake of natural or artificial sweeteners
      • Potential effect of such compounds on microbiota composition and subsequent effects on insulin resistance and NAFLD
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/

Fast food

Study published in Clinical Gastroenterology and Hepatology


Hepatic steatosis

  • Develops when the rate of fatty acid (FA) input is greater
    • Influx
    • Synthesis with subsequent esterification to TG
  • Than the rate of FA output
    • Oxidation
    • Outflux - very low-density lipoprotein (VLDL) secretion
  • Inhibition of peripheral 5-HT synthesis
    • Prevents obesity and metabolic dysfunction
    • By increasing energy expenditure in BAT and beige adipocytes in inguinal white adipose tissue
  • d-nb.info/1173570659/34

Fruktoza

  • In the liver, fructose is poorly metabolized by glucokinase (GCK)
    • Being hepatic fructose oxidation
    • Mainly driven by the action of ketohexokinase (KHK or fructokinase)
  • KHK starts fructose degradation,
    • Leading to a faster metabolization of fructose compared to glucose
      • Less-regulated steps of fructolysis compared to the highly regulated phosphorylation steps of glycolysis
  • Production of 3-carbon metabolites of fructose by ALDOB (glyceraldehyde and dihydroxyacetone-P)
    • Are in equilibrium with
      • Glycerol 3-phosphate synthesis
      • De novo fatty acid synthesis used in triglyceride generation
  • Fructose in the liver suppresses fatty acid oxidation
    • Via inhibition of malonyl-CoA on fatty acid transport to mitochondria
  • Enhanced de novo lipogenesis is amplified by the induction by
    • Fructose of Carbohydrate-Responsive Element–Binding Protein (ChREBP; also stimulated by glucose)
    • Sterol Regulatory Element–Binding Protein 1c (SREBP1c; mainly stimulated by insulin)
  • Fructose-1P, the product of KHK reaction
    • Indirectly induces the use and phosphorylation of glucose in the liver
      • Via interaction with the GCK regulatory protein
      • Leading to accelerated glycogen synthesis
  • Fructose degradation is also related to
    • Rapid Pi and ATP depletion
      • Due to phosphorylation of glucose by KHK
        • Which increases uric acid production by activation of AMP catabolism
  • Uric acid
  • Fructose
    • Activate a higher secretion of the hepatokyne Fibroblast-Growth-Factor-21 (FGF21)
      • Involved in the regulation of insulin sensitivity,
      • Intrahepatic lipid accumulation
      • Macronutrient selection
  • High consumption of fructose
    • Is involved in the activation of de novo lipogenesis
    • Inhibition of fatty acid oxidation
    • Hepatic acceleration of glycogen synthesis
    • Promotion of insulin resistance
    • Hyperuricemia,
    • Increased postprandial lipemia
    • Development of NAFLD
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/
  • Fructose also has an endogenous biosynthetic pathway
    • Initiated by the conversion of glucose to sorbitol
    • Catalyzed by the NADPH-dependent enzyme aldose reductase (AR)
    • Followed by the action of NAD-dependent sorbitol dehydrogenase
  • Believed to be a minor metabolic fate for glucose
    • Except in hyperglycemic status,
      • Linked to diabetes complications
  • Fructose-induced hyperuricemia
    • Upregulates KHK and simultaneously activates AR
      • Leading to increased endogenous fructose synthesis
        • Leading to excessive intrahepatic accumulation

Studies conducted in children and adolescents

  • Glucose and fructose are energetically matched
  • Found together either in sucrose and HFCS
  • Difficult to disentangle their separate effects on NAFLD and chronic diseases in human studies

Analysis of prospective studies

  • Association between SSB intake with increased metabolic syndrome risk was not extended to other important sources of dietary fructose
  • Excessive weight gain in children is promoted by SSBs
    • Induced by its high caloric content
  • Dietary energy excess is the primary factor associated with NAFLD
    • Unique features of fructose metabolism in the liver suggests a role of fructose intake in intrahepatic fat accumulation
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/


Fruktóza a glukózofruktózový sirup

  • Ale i další sacharidy v nadbytku
  • Každý venkovan ví, jak se cpou husy šiškami z brambor a pšeničné mouky, aby měly na vánoce hezky tučná játra
  • Tohle považuji za hlavní příčinu všeho
  • Nejhorší jsou sladké nápoje a pak jakákliv potravina s přidaným cukrem, obzvláště glukozo-fruktozovou legrací
  • Za současnou epidemmi je zodpovědná konzumace těchto sajrajtů již od dětského věku

Schwarz et al. 2017, USA Obese Children (9–18 years old; n = 41)

  • With habitual high sugar consumption
  • 9 days of isocaloric fructose restriction
  • Reductions in liver fat, visceral fat and DNL after fructose restriction

Jin et al., 2012, USA Nine children with NAFLD and 10 matched controls without NAFLD (11–18 years old)

  • 24-h periods of isocaloric macronutrient-balanced meals with either a fructose beverage or a glucose beverage
  • Effects of fructose on plasma lipids occurred in both healthy and NAFLD children, being the latter more sensitive to fructose actions

Jin et al. , 2014, USA As in Jin et al.

  • Endotoxin levels in NAFLD increased after fructose beverages compared to healthy children.

As in Jin et al.

  • Endotoxin levels in NAFLD increased after fructose beverages compared to healthy children.

Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction

Metin Basaranoglu1, Gokcen Basaranoglu2, Elisabetta Bugianesi

Obesity-associated protein (FTO)

  • Expression was obviously elevated in the livers of mice and humans with hepatic steatosis
    • V.s. due to its decreased ubiquitination

FTO overexpression in HepG2 cells

  • Induced triglyceride accumulation

FTO knockdown

  • Exerted an opposing effect

Adeno-associated viruses 8 (AAV8)-mediated FTO overexpression in the liver

  • Promoted hepatic steatosis in C57BL/6J mice
  • FTO inhibited the mRNA of peroxisome proliferator-activated receptor (PPAR) in hepatocytes

Activation of PPAR by its agonist GW7647

  • Reversed lipid accumulation in hepatocytes induced by FTO overexpression


Furosemide and spironolactone


Serum gamma-linolenic acid = riziková, omega 6 = protektivní, PUFA3 nesignifikantní

  • Body converts to GLA

Cross-sectional and longitudinal among middle-aged and older men and women from eastern Finland

  • Associations of serum n-3 (omega-3) and n-6 (omega-6) PUFAs with NAFLD
  • Analyses included
    • 1533 men examined in 1984-1989
    • 674 men and 870 women examined in 1998-2001 in the Kuopio Ischaemic Heart Disease Risk Factor Study
  • Longitudinal analyses included
    • 520 men examined in 1991-1993 and 301 men and 466 women examined in 2005-2008
  • Fatty liver index (FLI) was used as a surrogate for NAFLD.
    • Hepatic steatosis was defined as FLI nad 60.

Results

  • Participants with higher serum concentrations of total n-6 PUFA and linoleic acid, the major n-6 PUFA
    • Had markedly lower FLI
    • Lower odds for hepatic steatosis
  • Serum gamma-linolenic acid concentration
    • Associated with a higher FLI
    • Higher odds for hepatic steatosis
  • Other PUFAs
    • Were generally weaker and nonsignificant
  • Long-chain n-3 PUFAs
    • Had inverse associations
  • High estimated delta 5-desaturase activity
    • Was associated with lower risk
  • High estimated delta 6-desaturase activity
    • With higher risk for NAFLD
PMID: 35648467, PMCID: PMC9437980, DOI: 10.1093/ajcn/nqac150


Genetic variants linked to NASH risk

  • Heavily biased toward genes involved in the regulation of lipid metabolism
    • Hypothesis that NASH is fundamentally a metabolic disease
  • pubmed.ncbi.nlm.nih.gov/33346069/
  • Geny nejsou osud.

H. pylori-related MAFLD

  • Largely depends on fetuin A and lipoproteins
  • H. pylori-positive patients exhibited
    • Higher Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scores
    • Fasting insulin serum levels compared to H. pylori-negative patients (Eshraghian et al. 2009).
  • H. pylori IgG seropositivity has been associated with
    • Hepatocyte ballooning (Sumida et al. 2015)
      • Characteristic of NASH (Zanto et al. 2010)
    • Potential association between H. pylori infection and the progression of simple steatosis to NASH
  • Possible interaction H. pylori - MAFLD involves
    • Fetuin A
    • Alpha 2-HS glycoprotein (AHSG)
      • Serum glycoprotein synthesized by hepatocytes - carrier of free fatty acids

Higher serum fetuin A

  • In H. pylori-positive patients
  • Correlate with impaired insulin sensitivity and glucose tolerance
  • Stefan and Häring 2013; Trepanowski et al. 2015
  • Increased fetuin A serum levels and hepatic gene expression
    • Related to hepatic steatosis and NASH (von Loeffelholz et al. 2016; Kahraman et al. 2013)

In vitro studies using rodent myoblasts

  • Fetuin A inhibits tyrosine kinase activity of the insulin receptor
  • Blocks insulin-mediated glucose transporter type 4 (GLUT4) translocation
  • Blocks protein kinase B (Akt) activation
    • Promoting insulin resistance (Goustin et al. 2013)
  • Fetuin A also acts as an endogenous adaptor protein
    • For free fatty acid-mediated activation of TLR4 in mice
    • Activation of TLR4 typically results in an inflammatory response
      • NF-kappaB and c-Jun N-terminal kinase (JNK) signaling
  • Represent an alternative mechanism for steatohepatitis development during H. pylori infection
  • H. pylori infection could also contribute to
    • Gut barrier disruption
      • Translocation of LPS and other PAMPs to the liver (Dash et al. 2019; Quesada-Vázquez et al. 2020)
      • Known activators of Kupffer cells and stellate cells to promote fibrosis (Boeckmans et al. 2018)
  • H. pylori infection is associated with
    • Lower high-density lipoprotein (HDL) cholesterol serum values (Upala et al. 2016)
      • Promote dyslipidemia (Chatrath et al. 2012).

H. pylori eradication

  • Increases HDL
  • Decreases low-density lipoprotein (LDL) cholesterol (Niegawa et al. 2018)
  • Restoring the cardioprotective activity of the HDL/LDL ratio (Sun et al. 2016)
  • H. pylori eradication increases serum adiponectin levels (Ando et al. 2013)
    • Could enhance insulin sensitivity and lead to whole-body metabolic improvements (Ando et al. 2013; Stern et al. 2016)
  • link.springer.com/article/10.1007/s00204-021-03069-1

Increase in hepatocellular uptake of fatty acids


High-fat diet (HFD)

  • U zvířat vyvolá
  • Can mimic histological and metabolic abnormalities of human disease
  • Induce either up- or downregulation of the expression of genes and proteins that are involved in
    • Lipid metabolism,
    • Inflammation,
    • Oxidative stress,
    • Fibrogenesis pathways
  • HFD model
    • Occur after 24 weeks with insulin resistance
    • Appear to cause less severe fibrosis
  • pubmed.ncbi.nlm.nih.gov/35164140/

Human cytomegalovirus (CMV)

  • DNA virus belonging to the Herpesviridae family
  • Over 40% of the world population is infected
  • Persists latently throughout adulthood (Seitz 2010; Cannon et al. 2010).
  • CMV can replicate in multiple cell types
    • Epithelial cells of gland and mucosal tissue
    • Smooth muscle cells
    • Fibroblasts,
    • Macrophages,
    • Dendritic cells,
    • Hepatocytes
    • Vascular endothelial cells (Beltran and Cristea 2014).
  • CMV infection seems to be associated with the metabolic syndrome only in females
    • While normal weight CMV-immunoglobulin (Ig)G seropositive females exhibit a higher prevalence of dyslipidemia and metabolic syndrom
    • Not shared with females suffering from extreme obesity that surprisingly showed to have higher HDL- and lower LDL cholesterol (Fleck-Derderian et al. 2017).
  • CMV could promote MAFLD through de novo lipogenesis and oxidative stress

CMV-infected human fibroblasts

  • Increased activity of ACC
    • First rate-limiting enzyme in the de novo lipogenesis pathway
    • Regulated by SREBP-1c (Boeckmans et al. 2018).

Mice expressing CMV-derived regulatory protein IE2 (UL122)

  • Showed increased gene- and protein expression of SREBP-1c
    • Associated with hepatic steatosis (Zhang et al. 2018)
  • Increased hepatic SREBP-1c levels indeed correlate with hepatic steatosis
  • Decreased levels relate to advanced NASH (Nagaya et al. 2010)

Fibroblasts infected with CMV

  • Exhibit stressed mitochondria
    • Increased mass and membrane potential (Combs et al. 2019)
    • Could lead to oxidative stress and hence MAFLD progression
  • Intracellular CMV could induce (compensatory) anti-oxidative effects
  • CMV-infected human fibroblasts
    • Increase their production of enzymes that synthesize and utilize glutathione
    • Activate specific NF-E2 related factor 2 (Nrf2) target genes (Tilton et al. 2011; Lee et al. 2013; Lee 2018).
  • link.springer.com/article/10.1007/s00204-021-03069-1


Hypofunkce štítnice

  • Cross-talk between the thyroid and liver: a new target for nonalcoholic fatty liver disease treatment
  • PMID: 24363514 PMCID: PMC3857446 DOI: 10.3748/wjg.v19.i45.8238

Thyroid hormone (TH) and its receptors

  • Play a fundamental role in lipid metabolism and lipid accumulation in the liver
  • Thyroid receptor and its isoforms
    • Exhibit tissue-specific expression with a variety of functions
  • TRbeta1
    • Is predominantly expressed in the brain and adipose tissue
  • TRbeta2
    • Is the major isoform in the liver, kidney and fat
  • Lipid metabolism and lipid accumulation can be regulated and reversed by TH and its analogues.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC3857446/

Chronic activation of hypoxic signaling

  • Hypoxia-inducible factor (HIF)2alpha
    • Promotes NAFLD progression
      • Repressing genes involved in fatty acid beta-oxidation through unclear mechanisms
  • HIF2alpha promotes fatty liver and its physiological relevance in metabolic homeostasis.
  • Inhibiting autophagy using chloroquine
    • Did not decrease lipid contents in Vhl?Hep primary hepatocytes
  • Inhibition of ERK using MEK inhibitor
    • Decreased lipid contents in primary hepatocytes from a genetic model of constitutive HIF activation and primary hepatocytes loaded with free fatty acids.
    • Potentiated ligand-dependent activation of PPARalpha.
    • Improved diet-induced hepatic steatosis
      • Associated with the induction of PPARalpha target genes
  • pubmed.ncbi.nlm.nih.gov/33798787/


Coronavirus

COVID19

  • Admitted COVID-19 patients showed disturbed liver laboratory parameters (Zhang et al. 2020; Cui et al. 2004)
  • MAFLD patients are more prone to develop severe COVID-19
    • Have a longer viral shedding time (Ji et al. 2020).
  • ACE2 is expressed in cholangiocytes (Pawlotsky 2020)
  • COVID-19 patients show a higher occurrence of hepatic steatosis
    • Measured by thorax CT (Kreling et al. 2020)
  • Often accompanied by abnormal levels AST, ALT serum levels (Zhang et al. 2020; Cui et al. 2004)
  • Suffering from MAFLD increases the risk for developing severe COVID-19
    • In both diabetic and non-diabetic patients (Gao et al. 2020; Dongiovanni et al. 2020; Pan et al. 2020).
  • link.springer.com/article/10.1007/s00204-021-03069-1

MERS-CoV

  • Entry via DPP4
    • Expressed by hepatocytes (Baumeier et al. 2017)
  • Patients infected with MERS-CoV exhibit moderate liver steatosis
    • Scattered calcifications
    • Mild portal tract and lobular lymphocytic inflammation (Ng et al. 2020)
  • MERS-CoV can induce
    • Interleukin 1 receptor associated kinase 3 (IRAK-M),
    • Peroxisome proliferator-activated receptor (PPAR)-gamma
    • Interleukin (IL)-10 in macrophages
      • Lead to undesired immunosuppression
  • DPP4 inhibitors such as sitagliptin
    • Indicated for the treatment of insulin resistance and type 2 diabetes
    • Diabetes patients that take DPP4 inhibitors
      • Could be relatively protected against MERS-CoV infection (Al-Qahtani et al. 2017)
  • link.springer.com/article/10.1007/s00204-021-03069-1

Hepatitis C

  • Hepatitis C-induced steatosis disappears after successful antiviral treatment
  • While the ‘metabolic fat’ remains present (Asselah et al. 2006)
  • HCV particles bind onto low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL)
    • To form ‘lipo-viro-particles (LVP)
  • Viral entry
    • Scavenger receptor class B type I (SR-BI)
    • Cluster of differentiation (CD) 81
    • Claudin 1 (CLDN1) (Miao et al. 2017; Bugianesi et al. 2006)
  • Bind on diacylglycerol acyltransferase-1 (DGAT1)
    • With its nucleocapsid core
    • Accentuating the close tie between HCV infection and the lipid metabolism of liver cells (Herker et al. 2010).
  • Patients suffering from CHC
    • 11-times higher risk for developing type 2 diabetes in comparison to high-risk patients without CHC.
  • Suffering from CHC
    • Increase the risk for developing type 2 diabetes in patients without predisposing factors (Mehta et al. 2003)
  • Hepatic steatosis during chronic HCV infection
    • Stimulates necroinflammation and fibrosis (Adinolfi et al. 2001)
  • ‘HCV-associated dysmetabolic syndrome’ (Sheikh et al. 2008; Fletcher et al. 2008).
  • link.springer.com/article/10.1007/s00204-021-03069-1

Acquired immunodeficiency syndrome - AIDS

  • HAART-associated lipodystrophy induces insulin resistance and hepatic steatosis while also evoking mitochondrial toxicity
  • Ritonavir
    • Induce SREBP-1 and SREBP-2 translocation to the nucleus in mice
      • Promote lipogenesis and cholesterol biosynthesis
      • Could lay at the origin of fatty liver development (Riddle et al. 2001)
  • HAART can also alter growth hormone secretion that associates with lipodystrophy (Rochira and Guaraldi 2017)
  • Insulin resistance, along with induced lipodystrophy
    • Can lead to body fat redistribution and hepatic steatosis (Vallet-Pichard et al. 2012)
  • HIV-1 is known to suppress PPAR-gamma transcriptional activity and adipocyte differentiation (Shrivastav et al. 2008; Otake et al. 2004)
    • This mechanism can hence also contribute to the HAART-mediated lipodystrophy.
  • link.springer.com/article/10.1007/s00204-021-03069-1

Periodontitis

Helicobacter pylori (H. pylori)

Recurrent bacterial infections

  • A fatty liver is associated with recurrent bacterial infections
    • Independent of metabolic syndrome (Nseir et al. 2011)
  • Patients suffering from diabetes
    • Particular to those having type 1 diabetes (Carey et al. 2018)
  • link.springer.com/article/10.1007/s00204-021-03069-1

Yellow fever virus

Dengue virus

Hepatitis E virus



Inzulínová rezistence

  • NAFLD is strongly associated with
    • Central obesity,
    • Diabetes,
    • Dyslipidemia
    • Insulin resistance
  • Hepatic manifestation of the metabolic syndrome
    • Metabolic, inflammatory and oxidative stress processes, among others

3 key nutrients involved in pediatric NAFLD

Fruktóza - nadbytek

Omega-3 fatty acids - deficit

vitaminu E - deficit




Inzulínová resistance

  • Increased fat flux to the liver [1]
  • Etiopatogeneze NASH má shodné rysy s etiopatogenezí inzulinové rezistence a metabolického syndromu. [2]


Leaky gut syndrome

  • LPS toxin ze střev a jiné prozánětlivé stimuly
  • Dysmikrobie s převahou gramnegativních bakterií (vyšší schopnost proteolýzy)
    • Deficit kvasných bakterií
  • Játra jsou první orgán na cestě ze střeva
  • Chornické nadýmání, průjmy nebo zácpy
  • Chronické zánětlivé postižení gastrointestinálního traktu

Léčiva

  • Amiodarone,
  • Methotrexate,
  • Diltiazem,
  • Expired tetracycline,
  • Highly active antiretroviral therapy,
  • Glucocorticoids,
  • Tamoxifen
  • Environmental hepatotoxins
    • Phosphorus,
    • Mushroom poisoning
  • en.wikipedia.org/wiki/Fatty_liver_disease

Macrovesicular steatosis typically associated with


Manganese pollution to air and water

  • Significant threat to human health
  • Associations between manganese and liver stiffness and steatosis

Study of blood manganese with liver stiffness and steatosis in adults

  • 2017-2018 National Health and Nutrition Examination Survey (N = 4,192)
  • Subjects with excessive alcohol consumption and hepatitis B or C infection were excluded
  • Liver stiffness and steatosis were detected by transient elastography
  • Higher blood manganese concentrations
    • Were not associated with liver stiffness in the total sample and in males
  • Increased odds of significant liver fibrosis was found with higher blood manganese concentrations (tertile 3 vs. tertile 1) in females
    • [odds ratios (95% confidence intervals): 2.34 (1.32-4.14), P trend pod 0.01]
    • And in other races [1.47 (1.05-2.05), P trend = 0.03].
  • Higher blood manganese concentrations
    • Associated with liver steatosis in the
      • Total sample [1.33 (1.04-1.70), P trend = 0.03]
      • Females [1.58 (1.02-2.44), P trend = 0.04]
      • Other races [1.91 (1.50-2.43), P trend < 0.01]
      • Obese subjects [2.29 (1.13-4.65), P trend = 0.02]
  • Dose-response analysis
    • Observed associations were linear
  • Higher blood manganese concentrations were positively associated with liver stiffness and steatosis
    • Associations were mainly observed in females, in races other than Non-Hispanic White, and in obese subjects.
  • pubmed.ncbi.nlm.nih.gov/34651275/

Mercury

  • Association between Blood Mercury Levels and Non-Alcoholic Fatty Liver Disease in Non-Obese Populations
  • Cross-sectional data (n = 5919) from the Korean National Environmental Health Survey (2012–2014)
  • Blood mercury levels were log-transformed and divided into quartiles based on a weighted sample distribution.
  • Geometric mean of blood mercury in the overweight group
    • Was significantly higher than that of the non-obese group (p < 0.001)
  • Multivariate analysis, blood mercury levels were positively associated with NAFLD
    • For both the overweight and non-obese groups (all p for trend < 0.001)
  • Increased blood mercury levels
    • Are closely associated with NAFLD
  • In particular, mercury could be a risk factor for NAFLD in the non-obese population.
  • Humans are exposed to elemental mercury
    • Respiratory tract, inorganic mercury from food,
    • Methylmercury from seafood
  • The half-life of mercury in the blood is approximately 2 months
    • Cca 20 years in the brain
  • Blood mercury levels were 3.12 ug/L and 3.80 ug/L
    • In Korea, cca 4-6 times greater than those in the US and European countries
  • Increasing the adverse effects in the nervous, endocrine, and reproductive systems
  • Elevation of oxidative stress and alteration of mitochondrial functions
  • Liver enzyme levels found to be associated with mercury exposure in recent epidemiological studies
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8296250/

Metabolické příčiny

  • Abetalipoproteinemia,
  • glycogen storage diseases,
  • Weber–Christian disease,
  • Acute fatty liver of pregnancy,
  • Lipodystrophy
  • Malnutrition,
  • Total parenteral nutrition
  • Severe weight loss,
  • Refeeding syndrome,
  • Jejunoileal bypass,
  • Gastric bypass,
  • Jejunal diverticulosis with bacterial overgrowth
  • Celiac disease
  • Inflammatory bowel disease
  • Alpha 1-antitrypsin deficiency (?)
  • Otrava mochomurkou zelenou

Mitochondrial dysfunction




Poškození mitochondrií, blokáda enzymů, otrava

  • Játra (mzek, srdce, ledviny, svlay) mají enormní energetickou potřebu na detoxikační procesy, metabolismus lipidů aj.
  • Při deficity ATP nezbyde dost energie
    • Výsledkem může být hromadění se tukových látek do tukových kapének
  • Jedním z prvních projevů selhávání jater při akutní otravě je vznik steatozy
    • Která se však dál vyvíjí
  • Takže vznik steatozy, která nevede hned ke smrti a je chornická
    • By mohlo ukazovat na něco jako pomalou mírnou chronickou otravu

Na vině/rizikovým faktorem monou být:

  • Léky
  • Kontaminace ve stravě - nějaké toxické potřiky, herbicidy, ap.
  • Toxické látky v prostředí / v zaměstnání
    • Mohou být i ve vzduchu nebo pronikat kůží
  • Konzervanty
  • Barviva
  • Genetické mitochondriopatie

Induction of triglyceride (TG) lipolysis in adipose tissues


Naruseni cirkadialnich rytmu

  • Vede ke steatoze jater.

NSAIDs like Ibuprofen, and Naproxen


Obezita

  • Incidence of NAFLD in obese populations is increased by seven to tenfold relative to that in lean subjects
  • Obesity-associated inflammation, in particular inflammation in white adipose tissue (WAT)
    • Considered a critical factor that triggers or aggravates NAFLD
  • ajp.amjpathol.org/article/S0002-9440(21)00302-3/fulltext


Old / damaged cells / damaged mitochondria

Journal Nature Communications, report

  • Senescent or old cells in the liver store excessive fat because mitochondria,
  • The batteries of the cells, become damaged
    • Cannot effectively use the fat as a source of fuel, resulting in its storage.

Most vegetable oil and margarines


Low consumption of n-3 LCPUFAs and high n-6/n-3 ratios



Paradentoza

  • Periodontal disease and tooth loss are positively associated with liver diseases including
    • Nonalcoholic fatty liver disease (NAFLD),
    • Elevated transaminase level,
    • Liver cirrhosis and liver cancer
  • Multiple bacteria, including
    • H. pylori,
    • K. pneumoniae,
    • Chlamydia species
    • Bacteria involved in periodontitis
  • Can specifically contribute to the progression of MAFLD
Upala et al. 2016; Yuan et al. 2019; Bolukbas et al. 2005; Marangoni et al. 2015; Alakhali et al. 2018

Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans)

  • Gram-negative perio-pathogenic bacterium that has been linked to localized aggressive periodontitis (Arora et al. 2015)
  • Higher occurrence of A. actinomycetemcomitans was associated with periodontitis in type 1 and type 2 diabetes patients (Castrillon et al. 2015)
  • IgG seropositivity positively related with
    • Visceral fat,
    • Fasting plasma insulin levels
    • HOMA-IR score

Mice colonized with A. actinomycetemcomitans

  • Fed a high-fat diet (HFD)
  • Additional administration of A. actinomycetemcomitans led to higher hepatic steatosis
    • Compared to mice that did not receive the microorganism.
  • These mice also exhibited increased expression of genes related to
    • Glucagon and adipocytokine signaling
    • Insulin resistance along
    • Lower Akt phosphorylation (Komazaki et al. 2017)
  • link.springer.com/article/10.1007/s00204-021-03069-1

Porphyromonas gingivalis (P. gingivalis)

  • More common in the saliva of NASH patients (Yoneda et al. 2012)
  • Antibody titers against fimbriae type 4 relate to fibrosis severity (Nakahara et al. 2018)

Mice with dental P. gingivalis infection and fed with a HFD

  • Developed more severe steatosis and fibrosis in comparison to mice without the dental infection
  • Liver samples of mice with dental P. gingivalis infection
    • Exhibited lower stearoyl-CoA-desaturase (SCD1) and fatty acid elongase 6 (ELOVL6) levels
      • Inconsistent with the higher steatosis rate
  • Animals also showed increased hepatic levels of unsaturated fatty acids
    • Which might be seen as a protective and compensatory mechanism (Nakahara et al. 2018)
  • link.springer.com/article/10.1007/s00204-021-03069-1

Acetaminophen - Paralen

  • Snižje glutathion v játrech - antiox. ochranu

Plasmodium species, Schistosoma species, Toxoplasma gondii (T. gondii) and Trypanosoma cruzi (T. cruzi)

  • Are at the interface with MAFLD
Viriyavejakul et al. 2014; Chen et al. 2013; Huang et al. 2018; Lucchetti et al. 2019

Severe malaria cases

  • Often exhibit hepatic dysfunction and jaundice,
  • Which histopathologically manifest as
    • Hepatocyte necrosis,
    • Granulomatous lesions,
    • Kupffer cell hyperplasia,
    • Malarial pigmentation,
    • Cholestasis
    • Monocyte infiltrations to malarial nodules (Reuling et al. 2018).
  • Type 2 diabetes mellitus increases the risk for P. falciparum infection
    • Which might be due to decreased T cell-mediated immunity
    • Increased glucose availability for the parasite (Danquah et al. 2010; Muller et al. 2005)
  • P. falciparum infection is generally not associated with MAFLD progression.
  • Severe cases are accompanied by hyperplastic Kupffer cells and portal tract inflammation
    • Along with increased NF-?B p65 and cleaved caspase-3 expression in Kupffer cells and lymphocytes (Viriyavejakul et al. 2014)
  • Enlarged Kupffer cells have also been seen in the perivenular regions in human NASH liver biopsies (Lefkowitch et al. 2002)
  • Interplay between increased risk for P. falciparum infection and common hepatic histopathological features of NASH
    • Could result in an increased risk for synergetic liver disease progression.
  • Plasmodium merozoites
    • Require specific fatty acids that cannot be endogenously produced
      • Although essential for development and replication

Mice infected with P. chabaudi


Roundup residues in food cause fatty liver disease

  • Doses of glyphosate-based herbicides (GBH)

Rats administered for 2 years with 0.1 ppb

  • 50 ng/L glyphosate equivalent dilution
  • 4 ng/kg body weight/day daily intake of a Roundup GBH formulation
  • Showed signs of enhanced liver injury
    • Anatomorphological,
    • Blood/urine biochemical changes
    • Transcriptome profiling

Multiomic study combining metabolome and proteome liver analyses

  • Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in
    • Organonitrogen metabolism
    • Fatty acid beta-oxidation
  • Proteome disturbances reflected
    • Peroxisomal proliferation,
    • Steatosis
    • Necrosis
  • Metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05)
    • Confirmed lipotoxic conditions
    • Oxidative stress
    • An activation of glutathione and ascorbate free radical scavenger systems
  • Metabolite alterations
    • Associated with hallmarks of hepatotoxicity
  • Metabolome and proteome disturbances
    • Substantial overlap with biomarkers of non-alcoholic fatty liver disease
    • Progression to steatohepatosis
  • Confirmed liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.
Robin Mesnage, George Renney, Gilles-Eric Séralini, Malcolm Ward & Michael N. Antoniou. Scientific Reports 7, Article number: 39328 (2017) doi:10.1038/srep39328

Saturované tuky

  • Traduje se, že škodí a mají se zredukovat/uplně vysadit
  • Butter, ghee, margarine, cheese, full-fat dairy foods, and red meat

Serotonin and histamin

Microbial composition generated by a high-fat diet (HFD) or high-carbohydrate diet (HCD)

  • Release of metabolites derived from the microbiota
    • Promoting the development of metabolic diseases such as NAFLD

Release into the bloodstream of histamine or serotonin

  • Synthesized by intestinal mast cells
  • Enterochromaffin (EC) cell-derived serotonin
  • Also promote liver metabolic dysregulation, leading to steatosis and liver inflammation.
pdfs.semanticscholar.org/1061/8df0388556cc5483b31d0ec24e7c3e810c5c.pdf

In response to fasting

  • The 5-HT levels increase considerably
    • Overexpression of TPH1
  • High levels of 5-HT promote lipolysis in adipocytes
    • Generate substrates for hepatic gluconeogenesis
  • High levels of 5-HT
    • Modulate glucose metabolism,
    • Enhancing pancreatic insulin secretion
      • Rise to insulin resistance that promotes hepatic steatosis
  • May enhance hepatic carcinogenesis
  • Inhibition of hepatic serotonin receptor 2A (HTR2A) signaling in vivo by blocking the synthesis of 5-HT
    • Improves liver steatosis, hyperglycemia and dyslipidemia
  • pdfs.semanticscholar.org/1061/8df0388556cc5483b31d0ec24e7c3e810c5c.pdf


Peripheral serotonin

  • Peripheral serotonin
    • Accounts for 90% of serotonin in the body
    • Produced by enterochromaffin (EC) cells in the gastrointestinal tract
  • Bacteroides thetaiotaomicron heterologously expressing aadc of R. gnavus
    • Produced tryptamine in the mouse gut
    • Produced tryptamine increased anion and fluid secretion in the proximal colon via Serotonin receptor-4
      • Of the G protein-coupled receptors (GPCRs)
  • Gut bacteria modulate gastrointestinal motility and platelet function
    • By promoting peripheral serotonin production from EC cells
      • Mediated by tyramine and other gut bacterial metabolites
  • Aromatic amines produced by gut bacteria
    • Have a significant effect on host physiology
  • www.tandfonline.com/doi/full/10.1080/19490976.2022.2128605

Local serotonin concentrations in the portal blood


Spironolactone and vitamin E

  • Reduced NAFLD liver fat score, insulin, and HOMA-IR

ROLE OF PERIPHERAL 5-HT IN NAFLD

  • 5-HT2B receptor signaling during fasting
    • GDS promotes gluconeogenesis
    • Inhibits hepatic glucose uptake
    • GDS inhibits intrahepatocyte glucose uptake via a glucose transporter 2-dependent mechanism.

Several studies results

  • 5-HT in a dog model
    • boosted hepatic glucose uptake
    • Increased intrahepatic fat content
  • In ob/ob mice, the duodenal 5-HT content increased
    • Treatment with a 5-HT3 receptor antagonist
      • Reduced the elevated 5-HT levels while increasing SERT activity in the duodenum
      • reduced fat content, inflammation, and necrosis in these mice
  • Crane et al. intrahepatic role for peripheral 5-HT in mice fed an HFD
    • WT mice became obese and developed fatty liver disease when fed an HFD
    • Tph1-KO mice did not develop fatty liver on an HFD
      • Had reduced hepatic fat accumulation
  • Choi et al. - 5-HT as a therapeutic target for NAFLD
    • Gut-specific Tph1-KO and liver-specific Htr2a-KO mice
      • Were both resistant to HFD-induced hepatic steatosis
  • 5-HT2A antagonist sarpogrelate
    • ameliorated hepatic steatosis in HFD-fed mice
  • GDS regulates hepatic lipid accumulation through 5-HT2A receptor signaling
    • Htr2a-KO mice and WT littermates
      • gene sets related to inflammation, fibrosis, and steatohepatitis
        • Were significantly downregulated in the liver of the former.
  • 5-HT1A, 5-HT1F, 5-HT2A, 5-HT2B, and 5-HT7 receptors
  • 5-HT works in tandem with platelet-derived growth factor to promote HSC proliferation
  • In the diseased rat liver
    • 5-HT2B receptor was strongly associated with fibrotic tissue
    • 5-HT2 receptor antagonist treatment of HSC
      • reduced their proliferation
      • Increased their rate of apoptosis
  • In human HSC lines, 5-HT2A receptor antagonists
    • inhibited viability and wound healing
  • 5-HT2B receptor signaling
    • Activated HSC by increasing TGF-1 signaling
    • Inhibition of the 5-HT2B receptor
      • suppressed fibrogenesis and improved liver function in a murine carbon tetrachloride (CCl4)-induced cirrhosis model

HUMAN MOLECULAR BIOLOGY AND CLINICAL EVIDENCE OF THE ASSOCIATION BETWEEN 5-HT AND NAFLD

  • Genetics and molecular research using human samples
    • Potential roles for 5-HT signaling in NAFLD
    • MRNA expressions of 5-HT2A and 5-HT2B receptor in human omental adipose tissue
      • Were significantly increased in obese subjects compared to lean subjects
      • Positively correlated with serum aspartate aminotransferase and alanine aminotransferase levels
  • Levels of 5-hydroxyindoleacetic acid (5-HIAA; a metabolite of 5-HT)
    • Were significantly associated with hepatic events in NAFLD patients
  • Women with morbid obesity with normal liver histology x with NAFLD
    • Had decreased hepatic 5-HT2A and 5-HT2B receptor mRNA expressions
  • Pantano et al. - total RNA sequencing data
    • 5-HT2B receptor gene is one of the top 26 candidate genes related to the severity of liver fibrosis

Tricyclic antidepressant (TCAs), SSRIs, SNRIs, and 5-HT receptor agonists/antagonists

  • Regulate 5-HT signaling are widely used

Clinical studies have reported significant associations between the abovementioned drug classes and liver disease.

  • TCAs (imipramine, tianeptine) and SNRIs (venlafaxine, duloxetine)
    • Developed hepatic steatosis

A clinical study with SSRI fluoxetine

  • Increased serum triglyceride levels and hepatic lipid accumulation

A clinical trial on the cardiometabolic benefits of lorcaserin, a 5-HT2C receptor agonist

  • Lorcaserin significantly improved fatty liver in obese adults
  • Effect remained significant even after controlling for fat mass and change in body weight

5-HT

  • Plays a major role in regulating hepatic circulation and regeneration

Peripheral 5-HT

  • Promotes fat deposition and lipogenesis.
  • 5-HT induces hepatic fibrosis
  • Promotes HSC activation

Inhibition of peripheral 5-HT signaling

  • Impaired the development of NAFLD in animal models
  • Importance of 5-HT in liver disease

T. gondii

  • Protozoan parasite that latently encysts in multiple tissues
    • Including skeletal and cardiac muscle, retina, and the central nervous system (Mendez and Koshy 2017)
  • One-third to half of the world population is infected with T. gondii during lifetime (Flegr et al. 2014)

Population-based study


T. cruzi

  • Protozoan that causes Chagas disease

Infection in mice

  • Reduces hepatic steatosis
  • Exacerbates TLR4-mediated hepatic inflammation (Onofrio et al. 2015; Lucchetti et al. 2019; Cabalén et al. 2016)
    • Could worsen steatohepatitis
  • Metabolic syndrome also intensifies Chagas disease in mice during the acute phase of T. cruzi infection (Lucchetti et al. 2019)
  • Interrelationship between the metabolic syndrome, T. cruzi infection and MAFLD.
  • link.springer.com/article/10.1007/s00204-021-03069-1

Vitamin A vysoké dávky


Zánět, prozánětlivý stav

  • Není vázán pouze na obezitu
    • Existence of NAFLD, NASH, or even liver fibrosis in lean subjects
    • HIV-positive subjects with normal body mass index or lipodystrophy
  • Tissues additional to WAT are also involved in the pathogenesis of NASH.
  • ajp.amjpathol.org/article/S0002-9440(21)00302-3/fulltext

Worsen, NAFLD


Zuby zkažené a ztracené

  • Discovered an independent association between less frequent toothbrushing and a TE-established diagnosis of cirrhosis in NAFLD
  • In a separate investigation, Chen and colleagues discovered a correlation between tooth loss and an elevated risk of both NAFLD and liver cancer.


Increasing free fatty acid oxidation into the mitochondria

  • ß-oxidation promotes more adenosine triphosphate (ATP) consumption
  • Oxidative stress
  • Lipoperoxidation
  • Cellular damage
  • Increased ROS
    • Have increased levels of
      • Malonic dialdehyde
      • 4-hydroxynonenal
      • Tyrosine nitrated proteins
      • Hydroxydeoxyguanosine [1]
  • Activation of the immune system, vzestup:
    • TNF-alpha
    • TGF-beta
    • IL-8
    • IL-10 [1]
  • Activation of fibroblasts
    • Deposits of collagen I + IV [1]
      • Fibrosis
        • Cirhosis
          • Portal hypertension [1]
O úroveň výše

Poslední aktualizace: 30. 11. 2023 1:41:18