The emerging role of nuclear receptor ROR alpha and its crosstalk with LXR in xeno- and endobiotic gene regulation

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