title: Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation.
abstract: Farnesoid X receptor (FXR) is the master regulator of bile acid (BA) homeostasis because it controls BA synthesis, influx, efflux, and detoxification in the gut/liver axis. Deregulation of BA homeostasis has been linked to hepatocellular carcinoma (HCC), and spontaneous hepatocarcinogenesis has been observed in FXR-null mice. This dreaded liver neoplasm has been associated with both FXR gene deletion and BA-mediated metabolic abnormalities after inactivation of FXR transcriptional activity. In the present study, we addressed the hypothesis that intestinal selective FXR reactivation would be sufficient to restore the fibroblast growth factor 15 (FGF15)/cholesterol-7alpha-hydroxylase (Cyp7a1) enterohepatic axis and eventually provide protection against HCC. To this end, we generated FXR-null mice with re-expression of constitutively active FXR in enterocytes (FXR(-/-)iVP16FXR) and corresponding control mice (FXR(-/-)iVP16). In FXR-null mice, intestinal selective FXR reactivation normalized BA enterohepatic circulation along with up-regulation of intestinal FXR transcriptome and reduction of hepatic BA synthesis. At 16 months of age, intestinal FXR reactivation protected FXR-null mice from spontaneous HCC development that occurred in otherwise FXR-null mice. Activation of intestinal FXR conferred hepatoprotection by restoring hepatic homeostasis, limiting cellular proliferation through reduced cyclinD1 expression, decreasing hepatic inflammation and fibrosis (decreased signal transducer and activator of transcription 3 activation and curtailed collagen deposition).
  
  
  CONCLUSIONS
  Intestinal FXR is sufficient to restore BA homeostasis through the FGF15 axis and prevent progression of liver damage to HCC even in the absence of hepatic FXR. Intestinal-selective FXR modulators could stand as potential therapeutic intervention to prevent this devastating hepatic malignancy, even if carrying a somatic FXR mutation.
authors: National Cancer Research Center, IRCCS Istituto Oncologico "Giovanni Paolo II", Bari, Italy; Laboratory of Lipid Metabolism and Cancer, Fondazione Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy.
authors: Chiara
authors: C
authors: Degirolamo
authors: Salvatore
authors: S
authors: Modica
authors: Michele
authors: M
authors: Vacca
authors: Giuseppe
authors: G
authors: Di Tullio
authors: Annalisa
authors: A
authors: Morgano
authors: Andria
authors: A
authors: D'Orazio
authors: Kristina
authors: K
authors: Kannisto
authors: Paolo
authors: P
authors: Parini
authors: Antonio
authors: A
authors: Moschetta
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D015536:Down-Regulation; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018816:Genes, cdc; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001647:Bile Acids and Salts; D005346:Fibroblast Growth Factors; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C484722:Ahr protein, mouse; C108526:fibroblast growth factor 15, mouse