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

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 RORα (NR1F1) in regulating the oxysterol 7α-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of Cyp7b1 gene was suppressed in the RORα null (RORαsg/sg) mice, suggesting RORα as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of RORα, and transfection of RORα induced the expression of endogenous Cyp7b1 in the liver. Interestingly, Cyp7b1 regulation seemed to be RORα-specific, because RORγ had little effect. Reporter gene analysis showed that the activation of Cyp7b1 gene promoter by RORα was suppressed by LXRα (NR1H3), whereas RORα inhibited both the constitutive and ligand-dependent activities of LXRα. The mutual suppression between RORα and LXR was supported by the in vivo observation that loss of RORα increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR α and β isoforms showed activation of selected RORα target genes. Our results have revealed a novel role for RORα and a functional interplay between RORα and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis.

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