Jorge A. López-Velázquez, Ibrahim G. Castro-Torres, Vicente Sánchez-Valle, Nahum Méndez-Sánchez
Background & aims. Cholestasis is a liver disorder characterized by impaired bile flow, reduction 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 levels in a feedback mechanism, repressing hepatic cholesterol 7a-hydroxylase, the rate-limiting enzyme for the conversion of cholesterol to BA. This mechanism involves the hepatic nuclear receptor small heterodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. We investigated the role of activation of intestine-specific FXR in reducing hepatic levels of BA and protecting the liver from cholestasis in mice. Methods. We generated transgenic mice that express a constitutively active FXR in the intestine. Using FXR gain- and loss-offunction models, we studied the roles of intestinal FXR in mice with intrahepatic and extrahepatic cholestasis. 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 protected mice from obstructive extrahepatic cholestasis following bile-duct ligation or administration of anaphthylisothiocyanate. In Mdr2-/- mice, transgenic expression of activated FXR in the intestine protected against liver damage, whereas absence of FXR promoted progression of liver disease. Conclusions. Activation of FXR transcription in the intestine protects 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.