Intestinal nuclear bile acid receptor FXR and cholestasis

Autores: López Velázquez Jorge A, Castro Torres Ibrahim Guillermo, Sánchez Valle Vicente, Méndez Sánchez Nahum

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Article commented: Salvatore Modica, Michele Petruzzelli, Elena Bellafante, Stefania Murzilli, Lorena Salvatore, Nicola Celli, Giuseppe Di Tullio, Giuseppe Palasciano, Tarek Moustafa, Emina Halilbasic, Michael Trauner, Antonio Moschetta. Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis. Gastroenterology 2011; Doi:10.1053/j.gastro.2011.10.028. Original abstract 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 fro m 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 fro m 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 fro m cholestasis in mice by inducing FGF15 expression and reducing the hepatic pool of BA; this approach might be developed to reverse cholestasis in patients.

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2011-11-29   |   607 visitas   |   Evalua este artículo 0 valoraciones

Vol. 11 Núm.1. Enero-Febrero 2012 Pags. 152-154 Ann Hepatol 2012; 11(1)