RORα switches transcriptional mode of ERRγ that results in transcriptional repression of CYP2E1 under ethanol-exposure

초록

Increased cytochrome P450 2E1 (CYP2E1) expression is the main cause of oxidative stress, which exacerbates alcoholic liver diseases (ALDs). Estrogenrelated receptor gamma (ERR gamma) induces CYP2E1 expression and contributes to enhancing alcohol-induced liver injury. Retinoic acid-related orphan receptor alpha (ROR alpha) has antioxidative functions; however, potential cross-talk between ERR gamma and ROR alpha in the regulation of CYP2E1 has not been studied. We report that ROR alpha suppressed ERR gamma-mediated CYP2E1 expression. A physical interaction of ROR alpha with ERR gamma at the ERR gamma-response element in the CYP2E1 promoter was critical in this suppression. At this site, coregulator recruitment of ERR gamma was switched from coactivator p300 to the nuclear receptor corepressor 1 in the presence of ROR alpha. Cross-talk between ERR gamma and ROR alpha was demonstrated in vivo, in that administration of JC1-40, a ROR alpha activator, significantly decreased both CYP2E1 expression and the signs of liver injury in ethanol-fed mice, and this was accompanied by coregulator switching. Thus, this non-classical ROR alpha pathway switched the transcriptional mode of ERR gamma, leading to repression of alcohol-induced CYP2E1 expression, and this finding may provide a new therapeutic strategy against ALDs.

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