taurochenodeoxycholic-acid and Non-alcoholic-Fatty-Liver-Disease

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. The prevalence of NAFLD in Japan has nearly doubled in the last 10-15 years. Increasing evidence supports undernourishment in utero being causatively connected with the risk of NAFLD in later life. Low body mass index (BMI) has been common among Japanese women of childbearing age for several decades due to their strong desire to be thin. It is plausible that insufficient maternal energy intake by pregnant Japanese women may underlie the rapid increase in the prevalence of NAFLD in Japan. In order to clarify the mechanisms by which undernourishment in utero primes adult hepatic steatosis, we developed a mouse model of fetal undernourishment with a hepatic fat deposit-prone phenotype on an obesogenic high fat diet in later life. We found that endoplasmic reticulum (ER) stress response parameters were activated concomitantly with the deterioration of hepatic steatosis and also that the alleviation of ER stress with the chemical chaperone, tauroursodeoxycholic acid (TUDCA), significantly improved hepatic steatosis. Therefore, undernourishment in utero may program the future integration of ER stress in the liver on an obesogenic diet in later life and also induce the deterioration of hepatic steatosis. These results also provide an insight into interventions for the potential high-risk population of NAFLD, such as those born small or exposed to maternal undernourishment during the fetal period, with the alleviation of ER stress by dietary supplements and/or specific food including chaperones.

Topics: Adult; Animals; Body Mass Index; Diet, High-Fat; Disease Models, Animal; Embryo, Mammalian; Endoplasmic Reticulum Stress; Energy Intake; Female; Fetus; Humans; Japan; Liver; Malnutrition; Mice; Non-alcoholic Fatty Liver Disease; Pregnancy; Prenatal Exposure Delayed Effects; Taurochenodeoxycholic Acid

Silybin shows good effects against obesity and metabolic syndrome, but the systemic modulation effect of silybin has not been fully revealed. This study aims to investigate the metabolic regulation by silybin of nonalcoholic fatty liver disease (NAFLD). C57BL/6 J mice were fed a high-fat/high-cholesterol diet for 8 weeks and treated with silybin (50 or 100 mg/kg/day) and sodium tauroursodeoxycholate (TUDCA, 50 mg/kg/day) by gavage for the last 4 weeks. Blood biochemical indexes and hepatic lipid measurement as well as Oil red O staining of the liver were conducted to evaluate the model and the lipid-lowering effect of silybin and TUDCA. Furthermore, serum and liver samples were detected by a metabolomic platform based on gas chromatography-mass spectrometry (GC/MS). Multivariate/univariate data analysis and pathway analysis were used to investigate differential metabolites and metabolic pathways. The results showed that the mouse NAFLD model was established successfully and that silybin and TUDCA significantly lowered both serum and hepatic lipid accumulation. Metabolomic analysis of serum and liver showed that a high-fat/high-cholesterol diet caused abnormal metabolism of metabolites involved in lipid metabolism, polyol metabolism, amino acid metabolism, the urea cycle and the TCA cycle. Silybin and TUDCA treatment both reversed metabolic disorders caused by HFD feeding. In conclusion, a high-fat/high-cholesterol diet caused metabolic abnormalities in the serum and liver of mice, and silybin treatment improved hepatic lipid accumulation and modulated global metabolic pathways, which provided a possible explanation of its multiple target mechanism.

Topics: Animals; Cholesterol, Dietary; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Lipid Metabolism; Liver; Male; Metabolomics; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Silybin; Taurochenodeoxycholic Acid

The gut-liver axis is associated with the progression of non-alcoholic fatty liver disease (NAFLD). Targeting the gut-liver axis and bile acid-based pharmaceuticals are potential therapies for NAFLD. The effect of tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD, on intestinal barrier function, intestinal inflammation, gut lipid transport and microbiota composition was analysed in a murine model of NAFLD.. The NAFLD mouse model was established by feeding mice a high-fat diet (HFD) for 16 weeks. TUDCA was administered p.o. during the last 4 weeks. The expression levels of intestinal tight junction genes, lipid metabolic and inflammatory genes were determined by quantitative PCR. Tissue inflammation was evaluated by haematoxylin and eosin staining. The gut microbiota was analysed by 16S rRNA gene sequencing.. TUDCA administration attenuated HFD-induced hepatic steatosis, inflammatory responses, obesity and insulin resistance in mice. Moreover, TUDCA attenuated gut inflammatory responses as manifested by decreased intestinal histopathology scores and inflammatory cytokine levels. In addition, TUDCA improved intestinal barrier function by increasing levels of tight junction molecules and the solid chemical barrier. The components involved in ileum lipid transport were also reduced by TUDCA administration in HFD-fed mice. Finally, the TUDCA-treated mice showed a different gut microbiota composition compared with that in HFD-fed mice but similar to that in normal chow diet-fed mice.. TUDCA attenuates the progression of HFD-induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier function, decreasing intestinal fat transport and modulating intestinal microbiota composition.

Topics: Animals; Caco-2 Cells; Diet, High-Fat; Gastrointestinal Microbiome; Humans; Intestine, Small; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Random Allocation; Taurochenodeoxycholic Acid

Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mouse model. Additionally chronic HFD-fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH-HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD-induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down-regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.

Topics: Animals; Bile Acids and Salts; Carcinogenesis; Cell Line; Deoxycholic Acid; Diet, High-Fat; Female; Gastrointestinal Microbiome; Hep G2 Cells; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Pregnancy; Streptozocin; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurolithocholic Acid

Our objective was to investigate the role of bile acids in hepatic steatosis reduction after vertical sleeve gastrectomy (VSG).. High fat diet (HFD)-induced obese C57Bl/6 mice were randomized to VSG, Sham operation (Sham), Sham operation with pair feeding to VSG (Sham-PF), or nonsurgical controls (Naïve). All mice were on HFD until sacrifice. Mice were observed postsurgery and data for body weight, body composition, metabolic parameters, serum bile acid level and composition were collected. Further hepatic gene expression by mRNA-seq and RT-PCR analysis was assessed.. VSG and Sham-PF mice lost equal weight postsurgery while VSG mice had the lowest hepatic triglyceride content at sacrifice. The VSG mice had elevated serum bile acid levels that positively correlated with maximal weight loss. Serum bile composition in the VSG group had increased cholic and tauroursodeoxycholic acid. These bile acid composition changes in VSG mice explained observed downregulation of hepatic lipogenic and bile acid synthetic genes.. VSG in obese mice results in greater hepatic steatosis reduction than seen with caloric restriction alone. VSG surgery increases serum bile acids that correlate with weight lost postsurgery and changes serum bile composition that could explain suppression of hepatic genes responsible for lipogenesis.

Topics: Animals; Bile Acids and Salts; Caloric Restriction; Cholic Acid; Diet, High-Fat; Down-Regulation; Fatty Liver; Gastroplasty; Gene Expression Profiling; Gene Expression Regulation; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Postprandial Period; Random Allocation; Taurochenodeoxycholic Acid; Triglycerides; Up-Regulation; Weight Loss

Endoplasmic reticulum (ER) stress has been implicated in the development of nonalcoholic steatohepatitis. A methionine-choline-deficient (MCD) diet induces robust ER stress response and steatohepatitis, but the effects of ER stress modulation on the course of steatohepatitis remain uncertain. The present study evaluated whether reducing ER stress using the chemical chaperone tauroursodeoxycholic acid (TUDCA) could limit hepatocyte lipoapoptosis and progression of MCD diet-induced steatohepatitis.. HuH7 cells stably transfected with sodium taurocholate cotransporting polypeptide (HuH-Ntcp cells) and palmitate (PA) were used. Experimental steatohepatitis was induced in male C57BL/6 mice using an MCD diet, and three different doses of TUDCA (500, or 1,000 mg/kg, once daily; or 500 mg/kg twice daily) were administered by gavage from the start of the MCD diet regimen or after 4 weeks.. TUDCA reduced PA-induced ER stress as manifested by decreased eIF2α phosphorylation, XBP1 splicing and expression of BiP, ATF4, and CHOP in HuH-Ntcp cells. TUDCA also decreased PA-induced JNK phosphorylation, Puma up-regulation and Bax activation, which in turn suppressed caspase-dependent hepatocyte lipoapoptosis. Mice given TUDCA did not show a significant decrease in the intrahepatic triglyceride contents and steatosis. However, TUDCA treatment significantly reduced hepatic damage compared to controls for both early and late treatment groups. TUDCA treatment reduced the expression of ER stress markers and pro-apoptotic proteins, leading to decreased apoptosis and oxidative stress. Finally, TUDCA reduced histological fibrosis along with the down-regulation of pro-fibrotic gene expression in both early and late treatment groups.. These results show that TUDCA attenuates the progression of MCD diet-induced steatohepatitis by reducing ER stress.

Topics: Animal Feed; Animals; Apoptosis; Biomarkers; Choline Deficiency; Disease Progression; Drug Administration Schedule; Endoplasmic Reticulum Stress; Fatty Liver; Gastrointestinal Agents; Immunoblotting; Male; Methionine; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Taurochenodeoxycholic Acid

Hepatic steatosis continues to present a major challenge in liver transplantation. These organs have been shown to have increased susceptibility to cold ischemia/reperfusion (CIR) injury in comparison with otherwise comparable lean livers; the mechanisms governing this increased susceptibility to CIR injury are not fully understood. Endoplasmic reticulum (ER) stress is an important link between hepatic steatosis, insulin resistance, and metabolic syndrome. In this study, we investigated ER stress signaling and blockade in the mediation of CIR injury in severely steatotic rodent allografts. Steatotic allografts from genetically leptin-resistant rodents had increased ER stress responses and increased markers of hepatocellular injury after liver transplantation into strain-matched lean recipients. ER stress response components were reduced by the chemical chaperone taurine-conjugated ursodeoxycholic acid (TUDCA), and this resulted in an improvement in the allograft injury. TUDCA treatment decreased nuclear factor kappa B activation and the proinflammatory cytokines interleukin-6 and interleukin-1β. However, the predominant response was decreased expression of the ER stress cell death mediator [CCAAT/enhancer-binding protein homologous protein (CHOP)]. Furthermore, activation of inflammation-associated caspase-11 was decreased, and this linked ER stress/CHOP to proinflammatory cytokine production after steatotic liver transplantation. These data confirm ER stress in steatotic allografts and implicate this as a mediating mechanism of inflammation and hepatocyte death in the steatotic liver allograft.

Topics: Activating Transcription Factor 4; Animals; Caspases; Disease Models, Animal; Endoplasmic Reticulum; Fatty Liver; Heat-Shock Proteins; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Liver; Liver Transplantation; NF-kappa B; Non-alcoholic Fatty Liver Disease; Rats; Rats, Zucker; Reperfusion Injury; Signal Transduction; Stress, Physiological; Taurochenodeoxycholic Acid; Time Factors; Transcription Factor CHOP; Transplantation, Homologous