Benefit of Farnesoid X Receptor Inhibition in Obstructive Cholestasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 30; pp. 11323 - 11328
• Main Authors: Stedman, Catherine, Liddle, Christopher, Coulter, Sally, Sonoda, Junichiro, Alvarez, Jacqueline G., Evans, Ronald M., Downes, Michael
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25-07-2006; National Acad Sciences
• Subjects: Animals; Bile; Bile acids; Bile Acids and Salts - metabolism; Bile Ducts - pathology; Biological Sciences; Cholestasis; Cholestasis - drug therapy; Cholestasis - metabolism; Cholesterols; DNA-Binding Proteins - antagonists & inhibitors; Gene expression regulation; Genotypes; HDL lipoproteins; Hormones; Lipids - chemistry; Liver; Liver - injuries; Liver - pathology; Male; Medical disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Multidrug Resistance-Associated Proteins - metabolism; Proteins; Receptors; Receptors, Cytoplasmic and Nuclear; Rodents; Transcription Factors - antagonists & inhibitors; Triglycerides; Triglycerides - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0604772103

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 Mdrl, 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.