Taurin
Taurine
- Sterol regulatory element binding protein 1c (SREBP-1c)
- One of the major transcription factors for lipogenesis,
- Transcriptional activation of genes encoding some key enzymes during lipogenesis
- Fatty acid synthase (FAS),
- Acetyl-CoA carboxylase (ACC)
- Stearoyl-CoA desaturase (SCD)
2% taurine in water can downregulate in FXR-null mice with hepatic steatosis
- The mRNA expressions of SREBP-1c
- And its target genes of FAS and ACC in the liver of AFLD rat
- Significantly reduce the gene expression of ACC
- SCD1
Miyata et al., 2020a, Tang et al., 2019
- Expression of SREBP-1c in freshly isolated rat hepatocytes
- Was highly induced by insulin,
- The liver X receptor alpha (LXR)
- Critical in transcriptional activation of SREBP-1c
- taurine is a direct LXR ligand
- In hepatocytes, taurine significantly
- Induced Insig-2a levels
- Repressed nuclear translocation of SREBP-1c
- Resulting in a dose-dependent reduction in the cellular lipid levels (Hoang et al., 2012).
- SREBP-1c is regulated by multiple signaling pathways
- SREBP-1c expression can be promoted by
- Mammalian target of rapamycin complex 1
- Phosphorylated by insulin signaling pathway
- Inhibited by
- AMP-activated protein kinase (AMPK) pathway
- AMPK can enhance the activity of deacetylase
- By increasing the level of NAD+ in the cell
- To remove the acetyl groups on the 289th and 309th lysines of SREBP-1c, directly inhibit SPEBP-1c and reducing lipid production
- Sirtuin 1 (Sirt1)
- NAD-dependent deacetylase
- Beneficial roles in regulating hepatic lipid metabolism
- Controlling hepatic oxidative stress
- Mediating hepatic inflammation
- Deacetylating some transcriptional regulators
- Sirt1 can activate AMPK
- By regulating the upstream regulator of AMPK - liver kinase B1,
- Activated AMPK may increase the level of NAD+ in cells
- Feedback activates Sirt1 and finally inhibits the expression of SREBP-1c to control lipogenesis
- taurine reduced
- Serum liver TG levels
- Hepatic mRNA and protein levels of FAS and ACC-1
- By suppressing SREBP-1c and activating AMPK in NAFLD rat induced by high fat diet
- taurine restored hepatic lipid balance
- By activating Sirt1 in rat with steatohepatitis induced by cafeteria diet
- Carbohydrate response element binding protein (ChREBP)
- Glucose-activated transcription factor
- Controls lipogenesis in the liver via
- Lipogenic enzymes, such as FAS, ACC and SCD1 etc.
- Inhibition of either SREBP-1c or ChREBP
- Appears to be beneficial to alleviate hepatic steatosis.
- taurine effectively decreased whole body fat accumulation and serum and hepatic TG level
- But not repressing ChREBP in monosodium glutamate-induced obesity rats (Bonfleur et al., 2015)
- taurine inhibits lipogenesis
- By suppressing SREBP-1c rather than ChREBP.
- taurine mainly acts on SREBP-1c
- Downstream target genes FAS, ACC and SCD1 by activating Sirt1-AMPK pathway and LXR
- Thus inhibits lipogenesis to attenuate FLD.
- Taruine Promote energy expenditure and adaptive thermogenesis
- Promoting lipid consumption
- Mitochondrial fatty acid beta-oxidation
- Major route of lipid consumption in which free fatty acids (FFA) are esterified with CoA
- Transported into the mitochondria matrix,
- Oxidized to generate acetyl-CoA
- Carnitine palmitoyl transferase (CPT) system
- Mediates the transport of FFAs in mitochondrial beta-oxidation
- CPT1 is responsible for the initial enzymatic reaction for FFA transport
- Rate-limiting enzyme for fatty acid beta-oxidation
- Peroxisomes are involved in the beta-oxidation chain shortening of long-chain and very-long-chain fatty acyl-CoAs etc.
- Acyl-CoA oxidase (ACOX)
- First enzyme in the peroxisomal beta-oxidation process
- Genes encoding beta-oxidation pathway in liver
- Transcriptionally regulated by peroxisome proliferator-activated receptors
- An increase of CPT-1 mRNA levels
- In Sertoli cells of 20-day-old rats incubated with PPAR activators
- Mice deficient in fatty ACOX, microvesicular fatty change in liver cells was evident on the 7th day
- Livers showed extensive steatosis at 2 months of age
- MRNA and protein levels of genes regulated by PPAR were increased (Cook et al., 2001).
- Critical importance of PPAR and of peroxisomal fatty ACOX
- In energy metabolism
- In the development of hepatic steatosis
- Steatohepatitis (Pawlak et al., 2015, Reddy and Hashimoto, 2001).
In NAFLD hamster experiment, 0.7% taurine water significantly upregulated the gene expressions of hepatic PPAR? and uncoupling protein 2 (UCP2), which is the mitochondrial protein that plays a role in controlling energy expenditure by uncoupling respiration from ATP synthesis (Chang et al., 2011). These suggest that taurine may not only increase energy expenditure by promoting fatty acid beta-oxidation, but also increase adaptive thermogenesis. Actually, it has been reported that taurine markedly induced the browning of inguinal white adipose tissue of mice with significantly elevating expression of PPAR? co-activator 1 alpha (PGC1?), UCP1 and other thermogenic genes. Moreover, taurine treatment enhanced AMPK phosphorylation in vitro and in vivo experiment, and knockdown of AMPK?1 prevented taurine-mediated induction of PGC1? in C3H10T1/2 cells (Shao & Espenshade, 2012). These results reveal that taurine enhance adaptive thermogenesis by upregulating PGC1? and UCP1 etc. hermogenic genes via activating AMPK.
2.4. Inhibit cholesterol synthesis and promote cholesterol degradationCholesterol is also an important part of liver lipids. Cholesterol-lowering effect of taurine has been widely reported in many independent experiments performed by in vitro, animal and limited human studies (Chen et al., 2012, Chen et al., 2016), all which were mainly carried out through the following two aspects: inhibition of cholesterol synthesis and promotion of cholesterol biotransformation to bile acids.
In rat with AFLD induced by alcohol, pyrazole and high fat diet, 2% taurine water decreased hepatic TC by repressing gene expression of SREBP-2 and 3-hydroxyl-3-methylglutaryl-CoA reductase (HMGCR) which is the rate-limiting enzyme in cholesterol synthesis (Tang et al., 2019). SREBP-2, one of the key lipogenic transcription factors, primarily controls cholesterol biosynthesis, and is initially anchored (precursor protein) in the endoplasmic reticulum and then undergoes a cleavage process in the Golgi apparatus to transform into a nuclear active form. Finally it is transported to the nucleus to regulate its target genes such as HMGCR and low-density lipoprotein receptor (LDLR) (Sato, 2010, Shao and Espenshade, 2012). Studies have shown that AMPK inhibited SREBP-2 by suppressing its cleavage process and nuclear destination (Li et al., 2011). Combining with the results of Morsy MD’s experiment that taurine suppressed SREBP-1c and activated AMPK in NAFLD rat induced by high fat diet (Morsy & Abooq, 2020), all these data revealed that taurine may inhibit cholesterol biosynthesis by AMPK/SREBP-2/HMGCR pathway. It has also been reported that taurine significantly up-regulated gene expressions of liver LDLR in hamster with high-fat/cholesterol dietary, while taurine increased the binding of 125I–labeled LDL to LDLR by more than 50% in hamsters no matter on normal chow or high-fat diet. In addition, the LDL kinetic analysis showed taurine resulted in significant faster catabolic rate of plasma LDL fraction (Chang et al., 2011, Murakami et al., 2002). These results show that taurine not only inhibit cholesterol biosynthesis by AMPK/SREBP-2/HMGCR pathway, but also enhance the clearance of cholesterol from blood circulation to the liver by up-regulating LDLR, suggesting taurine promote the cholesterol degradation in the liver.
Studies have shown that taurine could promote the conversion of cholesterol to bile acid by improving the expression and activity cholesterol 7a-hydroxylase (CYP7A1) in hamster, rat and mouse on high fat/cholesterol diet, which is the rate-limiting enzyme in the classic pathway of cholesterol catabolism or bile acids biosynthesis (Chang et al., 2011, Chen et al., 2003, Chen et al., 2005). In vitro studies pointed out that taurine increased CYP7A1mRNA levels in H4IIE cell and HepG2 cell by activating LXR?, a nuclear receptor identified as a positive regulator of CYP7A1 transcription (Hoang et al., 2012). Furthermore, Guo J reported that taurine could enhance CYP7A1 expression to promote intracellular cholesterol metabolism by inducing hepatocyte nuclear factor 4? (HNF4?) and inhibiting phosphorylated c-Jun (p-c-Jun) and mitogen-activated protein kinase /extracellular signal regulated kinase (MEK) (Guo, Gao, Cao, Zhang, & Chen, 2017). HNF4? is considered to be the essential factor for the basal level expression of CYP7A1 while bile acids can activate the c-Jun N-terminal kinase (JNK) to phosphorylate c-Jun, and p-c-Jun binds to HNF4?, ultimately feedback inhibits CYP7A1 expression (De Fabiani et al., 2001, Li et al., 2006). In fact, cholesterol homeostasis is regulated by the conversion of cholesterol to bile acid and the feedback inhibition of bile acid on CYP7A1, and MEK also is one of the factors which can feedback repress CYP7A1 transcription (Chiang, 2009).
In summary, taurine can reduce hepatic lipid level to attenuate FLD mainly by activating Sirt1-AMPK pathway to inhibit lipogenesis, promoting fatty acid beta-oxidation and adaptive thermogenesis, and inhibiting cholesterol synthesis and promoting cholesterol degradation.
3. Antioxidant effect of taurine3.1. Increase the antioxidant enzymes and substancesLiver lipotoxicity is now generally recognized that it can lead to nonalcoholic steatohepatitis and kill hepatocytes mainly through mitochondrial injury and oxidative stress (Farrell, Haczeyni, & Chitturi, 2018). In AFLD, intense ingestion of ethanol has been linked to the production of reactive oxygen species (ROS) and oxidative stress is considered as one of the key driving factors of alcohol-induced liver injury (Louvet & Mathurin, 2015). Three vital antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), provide a defensive mechanism against oxidative damage, while glutathione (GSH), a key determinant of redox signaling, acts as an antioxidant and provides a secondary line of defense against intracellular free radicals and peroxides generated by oxidative stress (Lu, 2013). Lipid peroxidation is believed to be one of the most important parameters of oxidative stress and is estimated by detecting the concentration of malondialdehyde (MDA) (Tsikas, 2017).
It was reported that when Swiss mice were given with alcohol (2.5 g/kg bw), simultaneous administration of taurine (42.84 mg/kg·bw) for 24 h led to significant enhancement of activities of SOD, CAT and GSH-Px by 52.8%, 36.6% and 38.1% respectively, and 29.6% increase in GSH concentration, and 14.2% decrease in MDA level in the liver (Goc, Kapusta, Formicki, Martiniaková, & Omelka, 2019). When the experiment lasted for 14 days and 56 days, taurine could still effectively improved the above indexes, suggesting simultaneous intake of taurine along with ethanol partly attenuated the oxidative damage in the liver. In NAFLD model of C57BL/6J mice fed with a high-fat diet, 2% or 5% taurine water for 12 weeks suppressed the diet-induced reduction of hepatic SOD and CAT activities and GSH level, and the rise of MDA level, while in HepG2 calls loaded with fatty acids, taurine suppressed the production of ROS and the increase of thiobarbituric acid-reactive substances (TBARS), which represent the lipid peroxidation end products (Murakami et al., 2018). In addition, the excessive accumulation of iron in the liver is positively correlated with the severity of NAFLD (Britton, Subramaniam, & Crawford, 2016). In an iron-overload Kunming mice model, 0.1 mol/L taurine water (for 13 weeks) could markedly enhance the activities of SOD, CAT and GSH-Px in the liver and effectively prevent the increase of MDA (Zhang et al., 2014). These results showed that taurine was effective in alleviating hepatic steatosis by reducing oxidative stress via increasing the enzymatic and nonenzymatic antioxidants and repressing the lipid peroxidation.
3.2. Directly and indirectly inhibit oxidation agentsTaurine is abundant in phagocytic cells and provides protection against cytotoxicity caused by ROS. Taurine can directly react with HOCl and HOBr, the ROS generated from neutrophil myeloperoxidase system and eosinophil peroxidase system respectively, to form the more stable and less toxic products, taurine chloramine (TauCl) and taurine bromamine (TauBr). Tau-Cl has been shown to inhibit the production of superoxide anion (O2–radical dot) and nitric oxide (NO) and protect phagocytic cells from oxidative damage (Kim and Cha, 2009, Kim and Cha, 2014). Tau-Cl also can increase the expressions of cytoprotective antioxidant proteins, such as heme oxygenase 1 (HO-1), peroxiredoxin (PRX) and thioredoxin (TRX) in macrophages. In H2O2-induced murine macrophage RAW 264.7, the level of PRX-1 and TRX-1 in 0.5 mM Tau-Cl pretreated group are significantly higher than only H2O2 treated group (Jang, Piao, Cha, & Kim, 2009). In addition, it is indicated that Tau-Cl could directly bind to Kelch-like ECH association protein 1 (Keap1) and prevent the Keap1-driven degradation of nuclear factor E2-related factor 2 (Nrf2), resulting in stabilization and enhanced nuclear translocation of Nrf2 and upregulation of HO-1 expression. Further experiment revealed that TauCl stimulated efferocytosis of peritoneal macrophages isolated from either Nrf2 or HO-1 wild-type mice but not Nrf2 or HO-1 knockout mice, indicating TauCl facilitate resolution of inflammation by increasing the efferocytic activity of macrophages through Nrf2-mediated HO-1 upregulation (Kim et al., 2015). However, TauBr has attracted little attention because the extracellular concentration of bromide is lower than that of chloride. Indeed, in vitro studies showed that TauBr can be reduced by H2O2, resulting in the loss of oxidizing and brominating activity (Marcinkiewicz et al., 2005, Marcinkiewicz, 2010).
All these suggest that the direct antioxidant effect of taurine is reflected in the neutralization of oxidative toxic substances and subsequently its products also inhibit the ROS mainly by Keap-1/Nrf2/HO-1 pathway to exert indirect antioxidant and even anti-inflammatory effects.
3.3. Maintain mitochondrial structure and functionMitochondria is energy metabolism center of the cell, and the mitochondrial respiratory chain is the main source of ROS. Lipid peroxidation (LPO) is produced in the process of ROS attacking target polyunsaturated fatty acids on mitochondrial membranes, which can oxidize mitochondrial lipids and then damage the integrity and function of mitochondria (Xiao, Zhong, Xia, Tao, & Yin, 2017). Taurine is involved in many fundamental physiological functions, such as membrane stabilization and modulation of mitochondria function and cation transport (Lambert et al., 2015). It has been reported that taurine reduced hepatic ATP level in high fat diet-fed mice, while in HepG2 cells taurine ameliorated the fatty acid-induced disruption of the mitochondrial membrane potential (Murakami et al., 2018). Jamshidzadehn A et al. indicated that taurine treatment decreased mitochondrial swelling, ROS and LPO and restored mitochondrial ATP in brain and liver in the rat model with acute liver failure and hyperammonemia induced by hioacetamide. These data suggest taurine has sterling antioxidant activity and is a potential protective agent against acute liver failure and hyperammonemia-induced mitochondrial dysfunction and energy crisis (Jamshidzadeh et al., 2017).
An in vitro experiment, in which taurine was added to primary rat hepatocytes cultured with ethanol, revealed that taurine downregulated the expression of Bax, Fas, Fas ligand (FasL), caspase 3 and caspase 9, while up-regulated B-cell lymphoma-2 (Bcl-2) expression (Wu et al., 2018). Bcl-2 protein family, including Bax which promote apoptotic and Bcl-2 which inhibit apoptotic, control the intrinsic apoptotic pathway by mediating permeabilization of mitochondrial outer membrane, which is considered a key step in apoptosis (Pena-Blanco & García-Sáez, 2018). Fas is a membrane protein belonging to the death receptor family. Cross-linking of Fas by its ligand of FasL or agonistic anti-Fas antibodies induces apoptosis of cells expressing Fas on the membrane by triggering a cascade of caspases (Timmer, de Vries, & de Jong, 2002). These data suggest that the regulation of taurine on apoptosis-related factors is associated with its maintenance of membrane function by inhibiting ROS.
The in vivo experiment in which taurine was administrated to AFLD rats showed that taurine increased total antioxidant capacity (T-AOC), cytochrome c oxidase (COX) and NADH dehydrogenase (ND) in AFLD rat liver (Wu et al., 2018). ND and COX, also named as respiratory chain complexes I and III respectively, are considered to be the primary mitochondrial sources of superoxide generation. ND is the entry site into the respiratory chain, which transfers the electrons from NADH to coenzyme Q and oxidizes NADH to generate NAD+ (Ohnishi, Ohnishi, & Salerno, 2018). An increase in the ratio of mitochondrial matrix NAD+/NADH means a decrease in the production of superoxide in the mitochondrial. The compound GSH is often mentioned in relation to mitochondrial function, primarily for a role as redox scavenger. Its role as redox pair with oxidized glutathione (GSSG) [GSSG/GSH] is pivotal with regard to controlling the electrical or redox gradient across the mitochondrial inner-membrane (Hansen & Grunnet, 2013). It has been reported that taurine reduced the ratio of liver GSSG/GSH in streptozotocin-treated rats, and increased NAD+/NADH ratio and decreases oxidative stress in heart failure mice cardiomyocytes (Furfaro et al., 2012, Liu et al., 2020). Jong CJ et al. used taurine antagonist and taurine transport inhibitor, beta-alanine, to discuss the preventing effect of taurine on mitochondrial oxidant production (Jong, Azuma, & Schaffer, 2012). Their study showed that the exposure of isolated cardiomyocytes to medium containing beta-alanine for 48 h led to a 45% decrease in taurine content and the enhance of superoxide generation, 50–65% decline on activities of ND and COX, and 30% falling of oxygen consumption. Especially, beta-alanine exposure significantly reduced the expression levels of respiratory chain complex subunits, ND5 and ND6, while co-administration of taurine with beta-alanine largely prevented the mitochondrial effects of beta-alanine, suggesting the bottleneck in electron transport appears to be caused by impaired synthesis of key subunits of the electron transport chain complexes. Thus, taurine serves as a regulator of mitochondrial protein synthesis, thereby enhancing the activity of electron transport chain and protecting mitochondria against excessive superoxide generation (Jong et al., 2012).
In sum, the antioxidant mechanism of taurine may attributed to: improve the activity of the antioxidant defense by enhancing the activity of antioxidant enzymes and the level of antioxidant agent; directly neutralize ROS from phagocytes to form the products of Tau-Cl and Tau-Br which have antioxidant and even anti-inflammatory effects; enhance the activity of mitochondrial electron transport chain, protect mitochondrial membrane structure against excessive generation of ROS and superoxide, thereby maintaining the mitochondrial function and inhibiting apoptosis.
4. Anti-inflammation effect of taurine4.1. Reduce pro-inflammatory factors and increase anti-inflammatory factorsThe steatosis-induced inflammatory milieu mainly be marked by the increase of proinflammatory cytokines (IL-1beta, IL-6 and TNF-? et al.) and the decrease of anti-inflammatory cytokines (IL-10 et al.) and adiponectin. Adiponectin is a protective adipokine with the effects of antagonizing hepatic lipid accumulation, insulin-sensitizing, anti-inflammation and antifibrosis, which plays a pivotal role in the pathogenesis of NAFLD. Clinical studies indicated that drugs which can reduce the levels of inflammatory markers and elevate serum adiponectin level may provide a better treatment strategy for NAFLD (Ali Khan, Kapur, Jain, Farah, & Bhandari, 2017).
It has been reported that continuous intake of 3 g/d taurine for 6 weeks reduced the expression of serum and hepatic IL-1beta, IL-6 and TNF-? in Wister rats with chronic alcohol consumption (Lin et al., 2015), 0.250 g/kg·bw/d taurine for 12 weeks reduced the expression of liver IL-1beta, IL-6 and TNF-? in C57BL/6J mice with NAFLD caused by arsenic exposure (Qiu et al., 2018), and 0.5 g/kg·bw /d taurine for 12 weeks decreased TNF-? and IL-6 levels and increased IL-10 and adiponectin levels in NAFLD albino rats induced by cafeteria diet, a self-selected high-fat diet providing an excess of energy (AH Abd Elwahab et al., 2017). Kim KS et al. stated that Tau-Cl notably increased the expression of adiponectin and leptin by inhibiting STAT-3 signaling in IL-1beta-stimulated adipocytes, especially TauCl treatment more significantly modulated the expression of adipokines in adipocytes stimulated with IL-1beta than that of non-stimulated adipocytes, suggesting that taurine plays a significant role in modulating the expression of adipokines under inflammatory conditions (Kim et al., 2013). Furthermore, taurine can combine with ursodeoxycholic acid to produce taurine-binding bile acid of taurodeoxycholic acid (TUDCA), and 4-weeks’ TUDCA intake (1.0 g/kg·bw/d) also can decrease the levels of pro-inflammatory cytokines (including IL-1beta and IL-6) and chemokines (such as CCL2 and CCL4) in high fat diet-induced NAFLD C57BL/6J mice (Wang et al., 2018).
4.2. Regulate the inflammation-related signal pathwaysOne of the pathological of FLD is inflammation and closely related to intestinal barrier dysfunction. Lipopolysaccharide (LPS) is a component of Gram-negative bacteria, which through inflammatory cascade to induce excessive release of pro-inflammatory cytokines including TNF-? and IL-6 and the production of ROS by binding with Toll-like receptor 4 (TLR-4) on the surface of Küpffer cells (Ali Khan et al., 2017, Jong et al., 2012). FLD inflammation is mediated by a direct inflammatory cascade from the alcohol detoxification process in AFLD or from lipotoxicity in NAFLD and AFLD, and the indirect inflammatory cascade in response to LPS (Moreira et al., 2012, Park et al., 2014, Saad et al., 2016).
In chronic alcohol-fed rats liver, taurine (1 g/kg·bw) significantly decreased the proteins levels of inflammatory markers such as inducible nitric oxide synthase (iNOS) and C-reactive protein (CRP), increased the expressions of TLR-4 and its common signal adaptor molecule of myeloiddifferentiationfactor88 (MyD88), repressed 2 different downstream signaling of TLR-4/MyD88: phosphorylated-P38 (p-P38) and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), p-nuclear factor-?B (p-NF?B) and p-inhibitor of NF-?B (p-I?B) (Qiu et al., 2018). iNOS and CRP can be induced by various pro-inflammatory cytokines including IL-1beta, IL-6 and TNF-? (Szabo, Petrasek, & Bala, 2012). ERK1/2, P38 and c-Jun N-terminal kinase (JNK) are three distinct signaling of mitogen-activated protein kinases (MAPK) pathway (Sun et al., 2015). The inflammatory regulatory function of NF-?B and MAPK is achieved through its transcriptional control of large number of important pro- and anti-inflammatory factors, and which is also the way to further cascade amplification of inflammatory signals mediated by TLR-4 (Mandrekar & Szabo, 2009).
Liu L et al. stated that taurine significantly increased serum SOD activity and hepatic HO-1 protein expression in LPS-induced liver injury rats, while reduced liver protein expression of cyclooxygenase-2 (COX-2), p-NF?B and p-ERK. In addition, taurine pretreatment alleviated the infiltration of inflammatory cells in liver tissues and hepatic congestion (Liu et al., 2017). It has been demonstrated that the activation of NF-?B by LPS can upregulate the expression of COX-2 and the increased levels of p-ERK and JNK also promote COX-2 protein expression, while CO was confirmed as a catalytic product of HO-1 that can alleviate LPS-induced inflammation by suppression of NF-?B. These evidence suggested that taurine reduced NF-?B/COX-2 signaling by activation of HO-1/CO, subsequently to inhibit inflammation (Liu et al., 2017).
Studies have shown that the antifibrotic effect of taurine may be related to its inhibition of the activation and proliferation of hepatic stellate cells (HSCs). In order to clarify the molecular mechanism of taurine-induced HSC apoptosis, Liang XQ et al established a network including transcriptomic and protein–protein interaction data. Comprehensive network analysis showed that taurine promoted the apoptosis of HSCs via up-regulating transforming growth factor-beta1 (TGFB1) and then activating the p38 MAPK-JNK-Caspase9/8/3 pathway (Liang, Liang, Zhao, Wang, & Deng, 2019), suggesting that the effect of taurine on MAPK pathway is not only to regulate inflammatory response, but also is involved in promoting HSCs apoptosis and improving liver fibrosis.
In addition, taurine derivatives such as Tau-Cl and TUDCA, also exert anti-inflammatory effects. In phagocytes, Tau-Cl inhibits LPS-induced iNOS expression by direct inhibition of Ras activation, ERK1/2 phosphorylation and NF-?B activation and decreases the production of proinflammatory mediators (Kim & Cha, 2009). It is also reported that Tau-Cl enhanced the expression of adipokines through inhibition of the STAT-3 signaling pathway in differentiated human adipocytes stimulated by IL-1beta, and inhibited the production of pro-inflammatory substances in inflammatory cells (Kim and Cha, 2009, Kim et al., 2013). In high fat diet-induced NAFLD mice, TUDCA supplementation largely reversed the decrease in gut epithelial tight junction molecules (ZO-1 and claudin 4), inhibiting LPS from entering the liver, thereby exerting an anti-inflammatory effect (Wang et al., 2018).
In summary, the anti-inflammatory effect of taurine is mainly reflected in the following aspects: increase the expression of anti-inflammatory cytokines and adipokines, decrease the expression of pro-inflammatory cytokines, regulate TLR-4/MAPK and TLR-4/NF-?B pathways to influence the inflammatory production, and improve intestinal barrier function by increasing the level of tight junction molecules.
5. Regulatory effect of taurine on ethanol metabolism enzymesEthanol-mediated liver injury is one of the vital pathogenesis of AFLD (Dunn & Shah, 2016). Ethanol is mainly oxidized to acetaldehyde under the action of alcohol dehydrogenase (ADH), and then oxidized to acetic acid under the catalysis of acetaldehyde dehydrogenase (ALDH), while CAT and cytochrome P450 2E1 (CYP2E1) also play an auxiliary role in the oxidation of ethanol to acetaldehyde (Osna, Donohue, & Kharbanda, 2017). Long-term intake ethanol induces CYP2E1 expression, and higher CYP2E1 activity not only accelerates the metabolism of ethanol, but also increases ROS production, causing oxidative stress and metabolic damage to hepatocytes (Osna et al., 2017). In the research of Wu GF et al., 2% taurine increase the level of ADH and ALDH in ALD Wister rats (Wu et al., 2013). Devi SL et al examined the effects of taurine on the metabolism and detoxification of ethanol in rats treated with iron carbonyl (0.5%, w/w) and ethanol (6 g/kg·bw/d)). The significant increase of ADH and ALDH activities and the decrease of CYP2E1 activity in liver were observed in taurine-supplemented rats comparing to the model rats, suggesting hepatic damage and fibrosis were reduced by taurine (Devi, Viswanathan, & Anuradha, 2009). These data shows that taurine can accelerate ethanol metabolism, reduce the accumulation of ethanol in the liver and its damage effect, suggesting taurine has the potential for the treatment of alcoholic liver disease.
6. Conclusions and future perspectivesAlthough the inducing factors of AFLD and NAFLD are different, they have some similar manifestations, such as steatosis and steatohepatitis, which are mainly caused by lipotoxicity, oxidative damage and inflammation etc. Taurine prevents hepatic steatosis mainly due to inhibiting lipogenesis, promoting energy expenditure and adaptive thermogenesis, and affecting the synthesis and the degradation of cholesterol; prevents oxidative damage mainly by increasing enzymatic and nonenzymatic antioxidants, inhibiting ROS and protecting mitochondrial membrane structure; prevents inflammation by affecting the expression of pro-inflammatory and anti-inflammatory factors, inhibiting TLR-4 mediated signaling pathways and improving intestinal barrier function; and also prevents the liver from alcohol damage. There is a certain correlation between different beneficial effects of taurine, for example, protective effect on structure and function of mitochondrial membrane plays the critical role in promoting fatty acid beta-oxidation and adaptive thermogenesis, increasing effect on antioxidant enzymes activities and inhibiting effect on ROS also play a key role in inhibiting pro-inflammatory factors. Therefore, antioxidant effect can be considered as one of the most important basis for taurine to prevent FLD. The comprehensive beneficial effects of taurine to fatty liver are shown in Fig. 1.
Download : Download high-res image (379KB)Download : Download full-size imageFig. 1. The comprehensive figure explaining the beneficial effects of taurine to fatty liver. Steatosis, oxidative stress, inflammation are the common factors leading to the progression of FLD including AFLD and NAFLD. First, taurine prevents hepatic steatosis mainly due to inhibiting lipogenesis by repressing SREBP-1c and its downstream target genes of lipogenesis-related enzymes via activating Sirt1-AMPK pathway, promoting energy expenditure and adaptive thermogenesis by AMPK-PPAR? pathway, inhibiting cholesterol synthesis by AMPK/SREBP-2/HMGCR pathway, and promoting cholesterol degradation by activating CYP7A1; second, taurine prevents oxidative damage by increasing enzymatic and nonenzymatic antioxidants, neutralizing ROS directly and inhibiting ROS indirectly by Keap-1/Nrf2/HO-1 pathway via taurine derivatives, protecting structure and function of mitochondrial membrane from attacking of ROS and superoxide; third, taurine prevents inflammation by reducing pro-inflammatory factors, increasing anti-inflammatory factors, inhibiting NF?B/COX-2 and MAPK-JNK signaling mediated by TLR-4, and improving intestinal barrier function by increasing level of tight junction molecules; fourth, taurine prevents liver from alcohol damage by increasing the activities of ADH and ALDH and decreasing the expression and activity of CYP2E1. There is a certain correlation between different beneficial effects of taurine, antioxidant effect also play a key role in promoting fatty acid beta-oxidation and adaptive thermogenesis, in inhibiting pro-inflammatory factors, and in regulating alcohol metabolism enzymes.
Taurine is one of food ingredients and is also widely used as a food additive. Due to its variety of biological effects, taurine is considered to have great potential in the development and application of functional foods. It has been reported that 6 g/day of oral taurine (for 4 weeks) is safe and may reduce portal pressure in cirrhotic patients (Schwarzer et al., 2018); and risk assessment for taurine suggests that the evidence for the absence of adverse effects is strong at supplemental intakes up to 3 g/d (Shao & Hathcock, 2008). Although many in vivo and in vitro experiments suggest that taurine may be of health protecting or therapeutic value in reducing the risks associated with NAFLD and AFLD; the systematic studies are still needed to further reveal its molecular mechanisms, more importantly, more human studies are required to provide its effective doses on AFLD and NAFLD respectively.
