title: Farnesoid X receptor-dependent and -independent pathways mediate the transcriptional control of human fibroblast growth factor 19 by vitamin A.
abstract: 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.
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jahn
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Sutor
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
authors.forename: Donata
authors.initials: D
authors.lastname: Dorbath
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Weiß
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Götze
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.
authors.forename: Heike M
authors.initials: HM
authors.lastname: Hermanns
authors.affiliation: University Hospital Würzburg, Division of Hepatology, Würzburg, Germany; University Hospital Zürich, Division of Gastroenterology and Hepatology, Zürich, Switzerland. Electronic address: Geier_A2@ukw.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014801:Vitamin A / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D005346:Fibroblast Growth Factors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D014801:Vitamin A; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human
keywords: Bile acid; Farnesoid X receptor; Fibroblast growth factor 19; Nuclear receptor; Retinoic acid; Vitamin A