title: Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis.
abstract: OBJECTIVE
  Cholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BAs) 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 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme for the conversion of cholesterol to BAs. 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 BAs 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-of-function 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 BAs and changing the BA pool composition. Activation of intestinal FXR protected mice from obstructive extrahepatic cholestasis after bile duct ligation or administration of α-naphthylisothiocyanate. 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.
authors: Laboratory of Lipid Metabolism and Cancer, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
authors: Salvatore
authors: S
authors: Modica
authors: Michele
authors: M
authors: Petruzzelli
authors: Elena
authors: E
authors: Bellafante
authors: Stefania
authors: S
authors: Murzilli
authors: Lorena
authors: L
authors: Salvatore
authors: Nicola
authors: N
authors: Celli
authors: Giuseppe
authors: G
authors: Di Tullio
authors: Giuseppe
authors: G
authors: Palasciano
authors: Tarek
authors: T
authors: Moustafa
authors: Emina
authors: E
authors: Halilbasic
authors: Michael
authors: M
authors: Trauner
authors: Antonio
authors: A
authors: Moschetta
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002779:Cholestasis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011897:Random Allocation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D005346:Fibroblast Growth Factors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse; C502772:Cyp7a1 protein, mouse