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Identification of Oxysterol 7-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor (ROR) (NR1F1) Target Gene and a Functional Cross-Talk between ROR and Liver X Receptor (NR1H3)

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (T.W., H.G., S.B., S.K., S.R., W.X.); Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (H.S.K., M.A., A.M.J.); and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (E.E., S.C.S.)

The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of ROR (NR1F1) in regulating the oxysterol 7-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of Cyp7b1 gene was suppressed in the ROR null (ROR^sg/sg) mice, suggesting ROR as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of ROR, and transfection of ROR induced the expression of endogenous Cyp7b1 in the liver. Interestingly, Cyp7b1 regulation seemed to be ROR-specific, because ROR had little effect. Reporter gene analysis showed that the activation of Cyp7b1 gene promoter by ROR was suppressed by LXR (NR1H3), whereas ROR inhibited both the constitutive and ligand-dependent activities of LXR. The mutual suppression between ROR and LXR was supported by the in vivo observation that loss of ROR increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR and β isoforms showed activation of selected ROR target genes. Our results have revealed a novel role for ROR and a functional interplay between ROR and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis.

Address correspondence to: Dr. Wen Xie, Center for Pharmacogenetics, 633 Salk Hall, University of Pittsburgh, Pittsburgh, PA 15213. E-mail, wex6{at}pitt.edu; or Dr. Anton M. Jetten, Cell Biology Section, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. E-mail: jetten{at}niehs.nih.gov