title: Benefit of farnesoid X receptor inhibition in obstructive cholestasis.
abstract: The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually in pregnane X receptor KO mice with cholestasis. Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4. FXR KO mice also exhibit a biphasic lipid profile after bile duct ligation, with an increase in high-density lipoprotein cholesterol and triglycerides by day 6. The expression of apolipoprotein AV was reduced in these mice, implicating FXR in triglyceride regulation. We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4. This study strongly suggests a potential clinical role for FXR antagonists in the treatment of obstructive cholestatic liver disorders.
authors.affiliation: Department of Clinical Pharmacology, Molecular Pharmacology Laboratory, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney NSW 2145, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Stedman
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Sally
authors.initials: S
authors.lastname: Coulter
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sonoda
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: Alvarez
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000473:pathology; D002779:Cholestasis / Q000188:drug therapy / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000293:injuries / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008055:Lipids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C489540:Abcc4 protein, mouse