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

•Vitamin A (VitA) derivatives induce FGF19 expression in human enterocyte-like cells.•Direct transcriptional activation of FGF19 by VitA is mediated via RARs.•Direct activation of FGF19 by VitA is independent of the bile acid receptor FXR.•In addition, VitA indirectly stimulates FGF19 expression via FXR-dependent pathways.

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.

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