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 proliferator-actived receptor alpha in response to physiological conditions requiring increased fatty acid oxidation. Retinoic acid receptor-related receptor alpha (ROR alpha) 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 ROR alpha 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 ROR alpha in HepG2 cells resulted in increased expression and secretion of FGF21. Suppression of ROR alpha expression caused a decrease in FGF21 expression and secretion, suggesting that ROR alpha contributes to the basal expression of FGF21. These data suggest that one mechanism by which ROR alpha regulates lipid metabolism may be by modulation of FGF21 secretion. Furthermore, this study identifies a clear link between ROR alpha, a key regulator of the mammalian clock, and FGF21, an important hormone regulating glucose and lipid homeostasis.