Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic Iiver disease

Bile acids are synthesized from cholesterol only in hepatocytes.Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine.Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor(FXR)and cell surface G protein-coupled receptor TGR5.FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis.In addition,bile acid-activated cellular signaling pathways regulate metabolic homeostasis,immunity,and cell proliferation in various metabolically active organs.In the small and large intestine,gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects.In turn,bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity.Currently,bile acid-based therapies including systemic and intestine-restricted FXR agonists,TGR5 agonists,fibroblast growth factor 19 analogue,intestine FXR antagonists,and intestine apical sodium-bile acid transporter(ASBT)inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis(NASH).These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest.More recently,human and experimental alcoholic liver disease(ALD)has been associated with disrupted bile acid homeostasis.In additional,new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.

Liver-specific microRNA-185 knockout promotes cholesterol dysregulation in mice

Background:The liver plays a key role in regulating whole body cholesterol homeostasis.Hepatic cholesterol accumulation causes liver injury in fatty liver disease and hypercholesterolemia increases the risk of cardiovascular disease.MicroRNAs(miRNAs,miRs)have been shown to regulate various pathways in cholesterol metabolism.Recently,miR-185 has been shown to regulate sterol regulatory element-binding protein 2(SREBP2)and low-density lipoprotein receptor(LDLR)to modulate cholesterol syn-thesis and uptake.Materials and methods:The role of miR-185 in regulating diet-induced metabolic disorders were studied in liver-specific miRNA-185 knockout(L-miR-185 KO)mice.Results:L-miR-185 KO mice developed worsened hepatic steatosis upon high-fat high-cholesterol Western diet feeding with accumulation of triglyceride and cholesterol in the liver.In addition,L-miR-185 KO mice developed hypercholesterolemia upon Western diet feeding.Gene expression analysis showed that L-miR-185 KO mice did not show increased hepatic mRNA expression of SREBP2 or its targets LDLR and HMG-CoA reductase(HMGCR).Although expression of miR-185 mimic inhibited the mRNA of SREBP2,HMGCR and LDLR in HepG2 cells,miR-185 inhibitor did not increase the mRNA of SREBP2,HMGCR or LDLR in HepG2 cells.Conclusions:In conclusion,we reported that L-miR-185 KO mice were more sensitive to Western diet induced hepatic steatosis and hypercholesterolemia.The molecular mechanisms underlying these metabolic changes remain to be investigated in future studies.

Bile acid receptors link nutrient sensing to metabolic regulation

Non-alcoholic fatty liver disease(NAFLD)is a common liver disease in Western populations.Nonalcoholic steatohepatitis(NASH)is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation,which significantly increase the risk of end-stage liver and cardiovascular diseases.Unfortunately,there are no available drug therapies for NASH.Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes.Bile acids circulate between the liver and intestine,where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut.Bile acids also act as signaling molecules that regulate metabolic homeostasis and inflammatory processes.Many of these effects are mediated by the bile acid-activated nuclear receptor farnesoid X receptor(FXR)and the G protein-coupled receptor TGR5.Nutrient signaling regulates hepatic bile acid synthesis and circulating plasma bile acid concentrations,which in turn control metabolic homeostasis.The FXR agonist obeticholic acid has had beneficial effects on NASH in recent clinical trials.Preclinical studies have suggested that the TGR5 agonist and the FXR/TGR5 dual agonist are also potential therapies for metabolic liver diseases.Extensive studies in the past few decades have significantly improved our understanding of the metabolic regulatory function of bile acids,which has provided the molecular basis for developing promising bile acid-based therapeutic agents for NASH treatment.

Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis

Background and aims:Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis(NASH)treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients.Recently,we have shown that combining a gut-restricted apical sodium-bile acid transporter(ASBT)inhibitor GSK2330672(GSK)with adeno-associated virus(AAV)-mediated liver fibroblast growth factor 15(FGF15)overexpression provides significantly improved efficacy than either single treatment against NASH and liver fibrosis in a high fat,cholesterol,and fructose(HFCFr)diet-induced NASH mouse model.The beneficial effects of the com-bined treatment can be attributed to the markedly reduced bile acid pool that reduces liver bile acid burden and intestinal lipid absorption.The aim of this study is to further investigate if combining GSK treatment with the orally bioavailable obeticholic acid(OCA),which induces endogenous FGF15 and inhibits hepatic bile acid synthesis,can achieve similar anti-NASH effect as the GSKþAAV-FGF15 co-treatment in HFCFr-diet-fed mice.Materials and methods:Male C57BL/6J mice were fed HFCFr diet to induce NASH and liver fibrosis.The effect of GSK,OCA,and GSKþOCA treatments on NASH development was compared and contrasted among all groups.Results:Findings from this study showed that the GSKþOCA co-treatment did not cause persistent reduction of obesity over a 12-week treatment period.Neither single treatment nor the GSKþOCA co-treatment reduce hepatic steatosis,but all three treatments reduced hepatic inflammatory cytokines and fibrosis by a similar magnitude.The GSKþOCA co-treatment caused a higher degree of total bile acid pool reduction(~55%)than either GSK or OCA treatment alone.However,such bile acid pool reduction was insufficient to cause increased fecal lipid loss.The GSKþOCA co-treatment prevented GSK-mediated induction of hepatic cholesterol 7alpha-hydroxylase but failed to induce ileal FGF15 expression.GSK did not reduce gallbladder OCA amount in the GSKþOCA group compared to the OCA group,suggesting that ASBT inhibition does not reduce hepatic OCA distribution.Conclusions:Unlike the GSKþAAV-FGF15 co-treatment,the GSKþOCA co-treatment does not provide improved efficacy against NASH and liver fibrosis than either single treatment in mice.The lack of synergistic effect may be partly attributed to the moderate reduction of total bile acid pool and the lack of high level of FGF15 exposure as seen in the GSKþAAV-FGF15 co-treatment.

Pathogenesis of fatty liver diseases and hepatocellular carcinoma

The prevalence of fatty liver diseases has increased rapidly in recent years to about 25%worldwide.Fatty liver diseases are multi-faceted in pathogenesis,disease phenotype,and mechanism.It is important to understand disease pathogenesis and mechanism in order to develop effective and safe drug therapy for treating fatty liver diseases.Alcoholic fatty liver disease(AFLD,or alcohol associ-ated liver disease)and viral hepatitis have been the major causes of liver transplant,liver cancer,and death.

New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile

Cholesterol gallstone formation represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed.Lithogenic bile is mainly caused by persistent hepatic hypersecretion of biliary cholesterol and sustained cholesterol-supersaturated bile is an essential prerequisite for the precipitation of solid cholesterol monohydrate crystals and the formation of cholesterol gallstones.The metabolic determinants of the supply of hepatic cholesterol molecules that are recruited for biliary secretion are dependent upon the input-output balance of cholesterol and its catabolism in the liver.The sources of cholesterol for hepatic secretion into bile have been extensively investigated;however,to what extent each cholesterol source contributes to hepatic secretion is still unclear both under normal physiological conditions and in the lithogenic state.Although it has been long known that biliary lithogenicity is initiated by hepatic cholesterol hypersecretion,the genetic mechanisms that cause supersaturated bile have not been defined yet.Identification of the Lith genes that determine hepatic cholesterol hypersecretion should provide novel insights into the primary genetic and pathophysiological defects for gallstone formation.In this review article,we focus mainly on the pathogenesis of the formation of supersaturated bile and gallstones from the viewpoint of genetics and pathophysiology.A better understanding of the molecular genetics and pathophysiology of the formation of cholesterol-supersaturated bile will undoubtedly facilitate the development of novel,effective,and noninvasive therapies for patients with gallstones,which would reduce the morbidity,mortality,and costs of health care associated with gallstones,a very prevalent liver disease worldwide.