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Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor–null mice by intestinal‐specific farnesoid X receptor reactivation
Author(s) -
Degirolamo Chiara,
Modica Salvatore,
Vacca Michele,
Di Tullio Giuseppe,
Morgano Annalisa,
D'Orazio Andria,
Kannisto Kristina,
Parini Paolo,
Moschetta Antonio
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27274
Subject(s) - farnesoid x receptor , enterohepatic circulation , cholesterol 7 alpha hydroxylase , medicine , endocrinology , small heterodimer partner , biology , fgf19 , homeostasis , g protein coupled bile acid receptor , nuclear receptor , cancer research , bile acid , receptor , transcription factor , fibroblast growth factor , biochemistry , gene
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). Conclusion : 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. (H epatology 2015;61:161–170)