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

Abstract

Retinoid-related orphan receptors (RORs), including the α, β and γ isoforms (NR1F1–3), are orphan nuclear receptors that have been implicated in tissue development, immune responses, and circadian rhythm. Although RORα and RORγ 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 RORα and/or RORγ 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 7α-hydroxylase (Cyp7b1), which plays a critical role in the homeostasis of cholesterol, as a RORα target gene. We showed that RORα is both necessary and sufficient for Cyp7b1 activation. Studies of mice deficient of RORα or liver X receptors (LXRs) revealed an interesting and potentially important functional crosstalk between RORα and LXR. The respective activation of LXR target genes and ROR target genes in RORα 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.