The farnesoid X receptor(FXR)is a nuclear receptor and transcriptional regulator activated by bile acids or synthetic FXR agonists.FXR is expressed highly in the liver and intestine where modulation of FXR critically ...The farnesoid X receptor(FXR)is a nuclear receptor and transcriptional regulator activated by bile acids or synthetic FXR agonists.FXR is expressed highly in the liver and intestine where modulation of FXR critically regulates the expression of genes involved in cholesterol and bile acid homeostasis,hepatic gluconeogenesis/lipogenesis,and inflammation.We review the roles of FXR and one of its intestinal target genes,fibroblast growth factor(FGF)15 in mice/FGF19 in humans,play in regulating these important pathways in health and diseases.The main purpose of this review is to review therapeutics that target bile acid signaling to treat non-alcoholic steatohepatitis(NASH),a stage of disease within the spectrum of non-alcoholic fatty liver disease(NAFLD)with a focus on current preclinical studies in mice and clinical research.NASH is a huge medical burden and characterized by hepatic steatosis,inflam-mation,and progressive development of liver fibrosis.However,there is currently no Food and Drug Administration approved treatment option for NASH.While there are multiple factors contributing to NASH pathophysiology,bile acid regulation is proposed to have a major role in NASH pathogenesis.Synthetic FXR agonists and FGF19 protein may be promising agents to treat NASH,with obeticholic acid(OCA),cilofexor,tropifexor,nidufexor,EDP-305,and NGM282 currently in phase II or III clinical trials of NASH.FXR antagonism has also emerged,and antagonists like ursodeoxycholic acid(UDCA)and glycine-beta-muricholic acid(Gly-MCA)are in pre-clinical stage development for NASH treatment.This mini review seeks to evaluate and organize the literature available on FXR ligands and pathways for the treatment of NASH.展开更多
Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of B...Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.展开更多
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 live...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.展开更多
基金Grant funding(USA National Institutes of Health:R01GM135258-GLG,R21ES029258-GLG,Veteran Administration:BX002741-GLG).
文摘The farnesoid X receptor(FXR)is a nuclear receptor and transcriptional regulator activated by bile acids or synthetic FXR agonists.FXR is expressed highly in the liver and intestine where modulation of FXR critically regulates the expression of genes involved in cholesterol and bile acid homeostasis,hepatic gluconeogenesis/lipogenesis,and inflammation.We review the roles of FXR and one of its intestinal target genes,fibroblast growth factor(FGF)15 in mice/FGF19 in humans,play in regulating these important pathways in health and diseases.The main purpose of this review is to review therapeutics that target bile acid signaling to treat non-alcoholic steatohepatitis(NASH),a stage of disease within the spectrum of non-alcoholic fatty liver disease(NAFLD)with a focus on current preclinical studies in mice and clinical research.NASH is a huge medical burden and characterized by hepatic steatosis,inflam-mation,and progressive development of liver fibrosis.However,there is currently no Food and Drug Administration approved treatment option for NASH.While there are multiple factors contributing to NASH pathophysiology,bile acid regulation is proposed to have a major role in NASH pathogenesis.Synthetic FXR agonists and FGF19 protein may be promising agents to treat NASH,with obeticholic acid(OCA),cilofexor,tropifexor,nidufexor,EDP-305,and NGM282 currently in phase II or III clinical trials of NASH.FXR antagonism has also emerged,and antagonists like ursodeoxycholic acid(UDCA)and glycine-beta-muricholic acid(Gly-MCA)are in pre-clinical stage development for NASH treatment.This mini review seeks to evaluate and organize the literature available on FXR ligands and pathways for the treatment of NASH.
基金the USA National Institutes of Health(NIH)(grant number:GM135258,ES029258)the Vet-erans Affair(grant number:BX002741).
文摘Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.
文摘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.
