Intestinal nuclear bile acid receptor FXR and cholestasis

Background & aims. Cholestasis is a liver di- sorder characterized by impaired bile flow, reduc- tion of bile acids (BA) in the intestine, and retention of BAs in the liver. The farnesoid X receptor (FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA le- vels in a feedback mechanism, repressing hepatic cholesterol 7a-hydroxylase, the rate-limiting enzyme for the conversion of cholesterol to BA. This mecha- nism involves the hepatic nuclear receptor small he- terodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. We investigated the role of activation of intestine-specific FXR in redu- cing hepatic levels of BA and protecting the liver from cholestasis in mice. Methods. Methods. Methods. Methods. We generated transgenic mice that express a constitutively active FXR in the intestine. Using FXR gain- and loss-of- function models, we studied the roles of intestinal FXR in mice with intrahepatic and extrahepatic cho- lestasis. Results.Selective activation of intestinal FXR induced FGF15 and repressed hepatic Cyp7a1, reducing the pool size of BA and changing the BA pool composition. Activation of intestinal FXR pro- tected mice from obstructive extrahepatic cholestasis following bile-duct ligation or administration of a- naphthylisothiocyanate. In Mdr2-/- mice, transgenic expression of activated FXR in the intestine protec- ted against liver damage, whereas absence of FXR promoted progression of liver disease. Conclusions. Conclusions. Conclusions. Conclusions. Activation of FXR transcription in the intestine pro- tects the liver from cholestasis in mice by inducing FGF15 expression and reducing the hepatic pool of BA; this approach might be developed to reverse cholestasis in patients. Abstract published under permission of Elsevier provided by Copyright Clearence Center Comment