title: Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters.
abstract: The farnesoid X receptor (FXR) plays critical roles in plasma cholesterol metabolism, in particular HDL-cholesterol (HDL-C) homeostasis. Obeticholic acid (OCA) is a FXR agonist being developed for treating various chronic liver diseases. Previous studies reported inconsistent effects of OCA on regulating plasma cholesterol levels in different animal models and in different patient populations. The mechanisms underlying its divergent effects have not yet been thoroughly investigated. The scavenger receptor class B type I (SR-BI) is a FXR-modulated gene and the major receptor for HDL-C. We investigated the effects of OCA on hepatic SR-BI expression and correlated such effects with plasma HDL-C levels and hepatic cholesterol efflux in hyperlipidemic hamsters. We demonstrated that OCA induced a time-dependent reduction in serum HDL-C levels after 14 days of treatment, which was accompanied by a significant reduction of liver cholesterol content and increases in fecal cholesterol in OCA-treated hamsters. Importantly, hepatic SR-BI mRNA and protein levels in hamsters were increased to 1.9- and 1.8-fold of control by OCA treatment. Further investigations in normolipidemic hamsters did not reveal OCA-induced changes in serum HDL-C levels or hepatic SR-BI expression. We conclude that OCA reduces plasma HDL-C levels and promotes transhepatic cholesterol efflux in hyperlipidemic hamsters via a mechanism involving upregulation of hepatic SR-BI.
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Bin
authors.initials: B
authors.lastname: Dong
authors.affiliation: Intercept Pharmaceuticals, Inc., San Diego, CA 92121.
authors.forename: Mark
authors.initials: M
authors.lastname: Young
authors.affiliation: Intercept Pharmaceuticals, Inc., San Diego, CA 92121.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Amar Bahadur
authors.initials: AB
authors.lastname: Singh
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304 Jingwen.Liu@va.gov.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics*; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D008076:Cholesterol, HDL / Q000378:metabolism*; D006224:Cricetinae; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D018955:CD36 Antigens; D008076:Cholesterol, HDL; D012333:RNA, Messenger; C464660:obeticholic acid; D002635:Chenodeoxycholic Acid
keywords: farnesoid X receptor; hepatocyte nuclear factor 4 α; high density lipoprotein cholesterol; low density lipoprotein receptor; scavenger receptor class B type I; sterol regulatory element-binding protein 2