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

作者：Jahn Daniel; Sutor Dominic; Dorbath Donata; Weiss Johannes; Goetze Oliver; Schmitt Johannes; Hermanns Heike M; Geier Andreas

来源：Biochimica et Biophysica Acta-Gene Regulatory Mechanisms, 2016, 1859(2): 381-392.

DOI：10.1016/j.bbagrm.2015.12.007

• Fibroblast growth factor 19
• Farnesoid X receptor
• Bile acid
• Nuclear receptor
• Vitamin A
• Retinoic acid

Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that controls bile add (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 add 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.

• 出版日期2016-2