Benefit of farnesoid X receptor inhibition in obstructive cholestasis.
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.
Stedman
Catherine
C
Department of Clinical Pharmacology, Molecular Pharmacology Laboratory, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney NSW 2145, Australia.
Liddle
Christopher
C
Coulter
Sally
S
Sonoda
Junichiro
J
Alvarez
Jacqueline G
JG
Evans
Ronald M
RM
Downes
Michael
M
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
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