Z Gastroenterol 2015; 53 - G3
DOI: 10.1055/s-0035-1558901

Vitamin A derivatives regulate fibroblast growth factor 19 expression in human enterocytes

D Jahn 1, D Sutor 1, J Schmitt 1, HM Hermanns 1, A Geier 1
  • 1University Hospital Würzburg (UKW), Division of Hepatology, Würzburg

Background: Human Fibroblast Growth Factor 19 (FGF19) and its mouse ortholog Fgf15 are gut-derived hormones with broad impact on bile acid (BA) and energy metabolism. FGF15/19 expression is induced by BA-mediated activation of the nuclear receptor (NR) FXR. Moreover, vitamin A (VA) has been shown to activate Fgf15 in an FXR/RXR-dependent manner in mice. Whether and how VA regulates FGF19 in humans is, however, currently unknown.

Methods: Human enterocyte-like HT-29 cells were treated with VA derivatives with distinct selectivity for nuclear retinoid receptors (RARs and RXRs). FGF19 mRNA and protein levels were measured by qPCR and ELISA, respectively. The contribution of FXR to VA-mediated FGF19 induction was assessed by siRNA-mediated knock down and immunofluorescence microscopy. In further mechanistic studies, the impact of Retinoic Acid Receptor γ (RARγ) on FGF19 was analyzed by various biochemical methods (e.g. siRNA and ChIP).

Results: FGF19 was strongly induced by the VA derivative 9-cis Retinoic Acid (9cisRA) which activates both types of retinoid receptors (RARs and RXRs). Interestingly, FGF19 activation was also found after treatment with all-trans RA or TTNPB (RAR-selective) but not Methoprene Acid (RXR-selective), indicating that RARs rather than RXRs regulate FGF19 in humans. Experiments with siRNAs demonstrated that VA-induced activation of FGF19 is mediated by RARγ. Moreover, RARγ binding to the distal FGF19 promoter was increased after treatment with 9cisRA pointing to a direct transcriptional activation independently of FXR. Consistently, knock down of FXR did not reduce FGF19 expression in 9cisRA-treated cells.

Conclusion: These findings point to an important role of VA derivatives as novel, FXR-independent regulators of FGF19 in human enterocytes. Given the broad metabolic functions of FGF19 and its well-documented dysregulation in enterohepatic disorders (e.g. NAFLD and IBD) this warrants further studies on the potential therapeutic usefulness of VA to modulate FGF19 levels in humans.