Publication Date:
2016-02-20
Description:
Increased cytochrome P450 2E1 (CYP2E1) expression is the main cause of oxidative stress, which exacerbates alcoholic liver diseases (ALDs). Estrogen-related receptor gamma (ERR) induces CYP2E1 expression and contributes to enhancing alcohol-induced liver injury. Retinoic acid-related orphan receptor alpha (RORα) has antioxidative functions; however, potential cross-talk between ERR and RORα in the regulation of CYP2E1 has not been studied. We report that RORα suppressed ERR-mediated CYP2E1 expression. A physical interaction of RORα with ERR at the ERR–response element in the CYP2E1 promoter was critical in this suppression. At this site, coregulator recruitment of ERR was switched from coactivator p300 to the nuclear receptor corepressor 1 in the presence of RORα. Cross-talk between ERR and RORα was demonstrated in vivo , in that administration of JC1–40, a RORα 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 RORα pathway switched the transcriptional mode of ERR, leading to repression of alcohol-induced CYP2E1 expression, and this finding may provide a new therapeutic strategy against ALDs.
Print ISSN:
0305-1048
Electronic ISSN:
1362-4962
Topics:
Biology
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