Farnesoid X receptor-dependent and -independent pathways mediate the transcriptional control of human fibroblast growth factor 19 by vitamin A.

Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that controls bile acid (BA)， carbohydrate and lipid metabolism. Whereas strong evidence supports a key role of BAs and farnesoid X receptor (FXR) for the control of FGF19 expression， information on other regulators is limited. In mice， FGF15 expression (ortholog of human FGF19) is induced by vitamin A (VitA) in an FXR-dependent manner. However， the significance of this finding for human FGF19 is currently unclear. Here， we demonstrate that VitA derivatives induce FGF19 in human intestinal cell lines by a direct transcriptional mechanism. In contrast to mouse FGF15， however， this direct regulation is not dependent on FXR but mediated by retinoic acid receptors (RARs) and their interaction with a novel DR-5 element in the human FGF19 gene. In addition to this direct effect， VitA derivatives impacted on the BA-mediated control of FGF19 by regulation of FXR protein levels. In conclusion， VitA regulates human FGF19 expression through FXR-dependent and -independent pathways. Moreover， we suggest that considerable mechanistic differences exist between humans and mice with regard to the nuclear receptors controlling the VitA-FGF15/19 axis. These findings may implicate a clinical relevance of RAR-activating VitA derivatives for the regulation of FGF19 levels in humans.