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MINIREVIEW

The Emerging Role of Nuclear Receptor ROR and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation

Taira Wada^*, Hong Soon Kang, Anton M. Jetten and Wen Xie^*,1

^* Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Cell Biology Section, Division of Intramural Research, The National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

To whom requests for reprints should be addressed at ¹ Center for Pharmacogenetics, University of Pittsburgh, 3501 Terrace St., 633 Salk Hall, Pittsburgh, PA 15261. E-mail: wex6{at}pitt.edu

Retinoid-related orphan receptors (RORs), including the , β and isoforms (NR1F1–3), are orphan nuclear receptors that have been implicated in tissue development, immune responses, and circadian rhythm. Although ROR and ROR have been shown to be expressed in the liver, the hepatic function of these two RORs remains unknown. We have recently shown that loss of ROR and/or ROR can positively or negatively influence the expression of multiple Phase I and Phase II drug metabolizing enzymes and transporters in the liver. Among ROR responsive genes, we identified oxysterol 7-hydroxylase (Cyp7b1), which plays a critical role in the homeostasis of cholesterol, as a ROR target gene. We showed that ROR is both necessary and sufficient for Cyp7b1 activation. Studies of mice deficient of ROR or liver X receptors (LXRs) revealed an interesting and potentially important functional crosstalk between ROR and LXR. The respective activation of LXR target genes and ROR target genes in ROR null mice and LXR null mice led to our hypothesis that these two receptors are mutually suppressive in vivo. LXRs have been shown to regulate a battery of metabolic genes. We conclude that RORs participate in the xeno- and endobiotic regulatory network by regulating gene expression directly or through crosstalk with LXR, which may have broad implications in metabolic homeostasis.

Key Words: nuclear receptor • gene regulation • metabolism