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