Modulation of Retinoic Acid Receptor-related Orphan Receptor {alpha} and {gamma} Activity by 7-Oxygenated Sterol Ligands [Gene Regulation] (Journal of Biological Chemistry)

The retinoic acid receptor-related orphan receptors and (ROR (NR1F1) and ROR (NR1F3)) are orphan nuclear receptors and perform critical roles in regulation of development, metabolism, and immune function. Cholesterol and cholesterol sulfate have been suggested to be ROR ligands, but the physiological significance is unclear. To date, no endogenous ROR ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both ROR and ROR by directly binding to their ligand-binding domains (Ki ~20 nm), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. One of the 7-oxygenated sterols, 7-hydroxycholesterol (7-OHC), serves as a key intermediate in bile acid metabolism, and we show that 7-OHC modulates the expression of ROR target genes, including Glc-6-Pase and phosphoenolpyruvate carboxykinase, in an ROR-dependent manner. Furthermore, glucose output from hepatocytes is suppressed by 7-OHC functioning as an ROR/ ligand. Thus, ROR and ROR are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols.