Potential conflict of interest: Nothing to report.
Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor–null mice by intestinal-specific farnesoid X receptor reactivation
Article first published online: 30 OCT 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 61, Issue 1, pages 161–170, January 2015
How to Cite
Degirolamo, C., Modica, S., Vacca, M., Di Tullio, G., Morgano, A., D'Orazio, A., Kannisto, K., Parini, P. and Moschetta, A. (2015), Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor–null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology, 61: 161–170. doi: 10.1002/hep.27274
The work was funded by Italian Association for Cancer Research (AIRC; IG 14732), the Italian Ministry of University and Education (Finanziamenti per la Ricerca di Base IDEAS RBID08C9N7; PRIN 2010FHH32M-002), the Italian Ministry of Health (Young Researchers Grants GR-2008-1143546 and GR-2010-2314703), and the University of Bari (IDEA GRBA0802SJ-2008).
Salvatore Modica is currently affiliated with the Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
Michele Vacca is currently affiliated with Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, UK and is a fellow of “Umberto Veronesi” Foundation at the University of Cambridge.
See Editorial on Page 21
- Issue published online: 29 DEC 2014
- Article first published online: 30 OCT 2014
- Accepted manuscript online: 20 JUN 2014 11:05AM EST
- Manuscript Accepted: 17 JUN 2014
- Manuscript Received: 8 OCT 2013
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. (Hepatology 2015;61:161–170)