Alcoholic liver disease is the most prevalent chronic liver disease. Melatonin is known to control many vital processes. Here, we explored a novel molecular mechanism by which melatonin-induced SIRT1 signaling protects against alcohol-mediated oxidative stress and liver injury. Gene expression profiles and metabolic changes were measured in liver specimens of mice and human subjects. Expression levels of Cb1r, Crbn, Btg2, Yy1, pro-inflammatory cytokines, and Cyp2e1 were significantly enhanced in chronic alcohol-challenged mice and human subjects. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic CYP2E1 protein, and reactive oxygen species (ROS) were elevated in alcohol-fed WT mice but not in Cb1r antagonist-treated, Crbn null, or Yy1-silenced mice. Importantly, alcohol-induced Yy1 and Cyp2e1 expression, ROS amount, and liver injury were markedly diminished by melatonin treatment and the transduction of Sirt1 in mice, whereas this phenomenon was prominently ablated by silencing of Sirt1. Notably, SIRT1 physically interacted with YY1 and attenuated YY1 occupancy on the Cyp2e1 gene promoter. Melatonin-SIRT1 signaling ameliorates alcohol-induced oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway. The manipulation of CRBN-YY1-CYP2E1 signaling network by the melatonin-SIRT1 pathway highlights a novel entry point for treating alcoholic liver disease.

中文翻译：

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褪黑素诱导SIRT1通过破坏CRBN-YY1-CYP2E1信号通路改善酒精介导的氧化性肝损伤。

酒精性肝病是最普遍的慢性肝病。众所周知，褪黑素可控制许多重要过程。在这里，我们探索了褪黑激素诱导的SIRT1信号转导保护免受酒精介导的氧化应激和肝损伤的新型分子机制。在小鼠和人类受试者的肝脏样本中测量基因表达谱和代谢变化。Cb1r，Crbn，Btg2，Yy1，促炎细胞因子和Cyp2e1的表达水平在慢性酒精挑战的小鼠和人类受试者中显着提高。酒精喂养的野生型小鼠的血清丙氨酸氨基转移酶（ALT），天冬氨酸氨基转移酶（AST），肝CYP2E1蛋白和活性氧（ROS）水平升高，但在Cb1r拮抗剂治疗，Crbn无效或Yy1沉默的小鼠中未升高。重要的是，酒精诱导的Yy1和Cyp2e1表达，褪黑素治疗和Sirt1的转导可显着降低ROS的含量和肝损伤，而沉默Sirt1可显着消除这种现象。值得注意的是，SIRT1与YY1物理相互作用，并减弱了Cyp2e1基因启动子上的YY1占有率。褪黑素-SIRT1信号转导通过破坏CRBN-YY1-CYP2E1信号转导通路来改善酒精诱导的氧化性肝损伤。褪黑素-SIRT1途径对CRBN-YY1-CYP2E1信号网络的操纵突出了治疗酒精性肝病的新切入点。褪黑素-SIRT1信号转导通过破坏CRBN-YY1-CYP2E1信号转导通路来改善酒精诱导的氧化性肝损伤。褪黑素-SIRT1途径对CRBN-YY1-CYP2E1信号网络的操纵突出了治疗酒精性肝病的新切入点。褪黑素-SIRT1信号转导通过破坏CRBN-YY1-CYP2E1信号转导通路来改善酒精诱导的氧化性肝损伤。褪黑素-SIRT1途径对CRBN-YY1-CYP2E1信号网络的操纵突出了治疗酒精性肝病的新切入点。