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

作　　者：David J.Matye Xuan Qin Mohammad Nazmul Hasan Lijie Gu Yung Dai Clayton Feng Li Tiangang Li 

机构地区：[1]Harold Hamm Diabetes Center,Department of Physiology,University of Oklahoma Health Sciences Center,Oklahoma City,OK,USA [2]Department of Pathology and Immunology,Baylor College of Medicine,Houston,TX,USA [3]NMR and Drug Metabolism Core,Baylor College of Medicine,Houston,TX,USA

出　　处：《Liver Research》2022年第4期276-283,共8页肝脏研究（英文）

摘　　要：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

关 键 词：Bile acids Farnesoid X receptor(FXR) Fibroblast growth factor 15(FGF15) Apical sodium-bile acid transporter(ASBT) Non-alcoholic steatohepatitis(NASH) Liver fibrosis 

分 类 号：R575.1[医药卫生—消化系统]