Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor α

Fibroblast growth factor 21 (FGF21) is a hormone produced by fat and the liver that plays an important role in lipid metabolism. FGF21 expression is induced by peroxisome proliferatoractived receptor α in response to physiological conditions requiring increased fatty acid oxidation. Retinoic acid receptorrelated receptor α(RORα) is another nuclear receptor that plays a critical role in lipid metabolism as well as in regulation of the circadian rhythm. In this study we demonstrate that RORα directly regulates the expression and secretion of FGF21. A canonical ROR response element was identified in the proximal promoter of the FGF21 gene and shown to exhibit functional activity. Overexpression of RORα in HepG2 cells resulted in increased expression and secretion of FGF21. Suppression of RORα expression caused a decrease in FGF21 expression and secretion, suggesting that RORα contributes to the basal expression of FGF21. These data suggest that one mechanism by which RORα regulates lipid metabolism may be by modulation of FGF21 secretion. Furthermore, this study identifies a clear link between RORα, a key regulator of the mammalian clock, and FGF21, an important hormone regulating glucose and lipid homeostasis.