Abstract
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.
Footnotes
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This work was supported in part by National Institutes of Health grants CA107011 and ES014626 (to W.X.) and by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (to A.M.J.). H.G. is supported by postdoctoral fellowship PDF0503458 from the Susan G. Komen Breast Cancer Foundation. Normal human hepatocytes were obtained through the Liver Tissue Procurement and Distribution System, which was funded by National Institutes of Health grant N01-DK70004/HHSN267200700004C.
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ABBREVIATIONS: ROR, retinoid-related orphan receptor; RORE, retinoid-related orphan receptor response element; LXR, liver X receptor; kb, kilobase(s); tk, thymidine kinase; Pcp2, Purkinje cell protein 2; Luc, luciferase; WT, wild type; bp, base pair(s); PCR, polymerase chain reaction; PEI, polyethylenimine; MEM, minimal essential medium; β-Gal, β-galactosidase; DMSO, dimethyl sulfoxide; RT, reverse transcription; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation; LXRE, liver X receptor response element; SCR1, steroid receptor coactivator 1; VP, viral protein 16; DKO, double knockout; UAS, upstream activation sequence.
- Received August 8, 2007.
- Accepted November 30, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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