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First published on November 30, 2007; DOI: 10.1124/mol.107.040741

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Received for publication August 8, 2007.
Revised November 30, 2007.
Accepted for publication November 30, 2007.

Identification of oxysterol 7{alpha}-hydroxylase (Cyp7b1) as a novel ROR{alpha} (NR1F1) target gene and a functional crosstalk between ROR{alpha} and LXR (NR1H3)

Taira Wada 1, Hoon Soon Kang 2, Martin Angers 2, Haibiao Gong 1, Shikha Bhatia 1, Shaheen Khadem 1, Songrong Ren 1, Ewa Ellis 1, Stephen Strom 1, Anton Jetten 2, Wen Xie 1*

1 University of Pittsburgh 2 National Institute of Environmental Health Sciences

* Address correspondence to: E-mail: wex6{at}pitt.edu

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 impact 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 appeared to be ROR{alpha}-specific, as 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. Reciprocally, 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.


Key words: Promoter analysis, Cytochrome P450, Knockout


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