Han Yong-Hyun, Kim Don-Kyu, Na Tae-Young, Ka Na-Lee, Choi Hueng-Sik, Lee Mi-Ock
From the College of Pharmacy and Bio-MAX institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Gwangju, Chonnam 500-757, Korea.
Nucleic Acids Res. 2016 Feb 18;44(3):1095-104. doi: 10.1093/nar/gkv1034. Epub 2015 Oct 12.
Increased cytochrome P450 2E1 (CYP2E1) expression is the main cause of oxidative stress, which exacerbates alcoholic liver diseases (ALDs). Estrogen-related receptor gamma (ERRγ) 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 ERRγ and RORα in the regulation of CYP2E1 has not been studied. We report that RORα suppressed ERRγ-mediated CYP2E1 expression. A physical interaction of RORα with ERRγ at the ERRγ-response element in the CYP2E1 promoter was critical in this suppression. At this site, coregulator recruitment of ERRγ was switched from coactivator p300 to the nuclear receptor corepressor 1 in the presence of RORα. Cross-talk between ERRγ 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 ERRγ, leading to repression of alcohol-induced CYP2E1 expression, and this finding may provide a new therapeutic strategy against ALDs.
细胞色素P450 2E1（CYP2E1）表达增加是氧化应激的主要原因，氧化应激会加剧酒精性肝病（ALD）。雌激素相关受体γ（ERRγ）诱导CYP2E1表达并促进酒精性肝损伤加重。维甲酸相关孤儿受体α（RORα）具有抗氧化功能；然而，ERRγ与RORα在CYP2E1调控中的潜在相互作用尚未得到研究。我们报告RORα抑制ERRγ介导的CYP2E1表达。RORα与CYP2E1启动子中ERRγ反应元件处的ERRγ发生物理相互作用对这种抑制作用至关重要。在此位点，在存在RORα的情况下，ERRγ的共调节因子募集从共激活因子p300转换为核受体共抑制因子1。ERRγ与RORα之间的相互作用在体内得到证实，即给予RORα激活剂JC1 - 40可显著降低乙醇喂养小鼠的CYP2E1表达和肝损伤迹象，并且这伴随着共调节因子的转换。因此，这种非经典的RORα途径改变了ERRγ的转录模式，导致酒精诱导的CYP2E1表达受到抑制，这一发现可能为ALD提供一种新的治疗策略。
