School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Department of Clinical Laboratory Medicine, The First Medical Centre, Medical School of Chinese People's Liberation Army, Beijing, China.
Int J Biol Sci. 2023 Mar 21;19(6):1831-1845. doi: 10.7150/ijbs.81447. eCollection 2023.
Besides abstinence, no effective treatment exists for alcohol-related liver disease (ALD), a dreaded consequence of alcohol abuse. In this study, we assessed the roles on ALD of dual specificity phosphatase-1 (DUSP1), an hepatoprotective enzyme, and Cullin-1 (CUL1), a member of the E3 ubiquitin ligase complex that exerts also transcriptional suppression of mitochondrial genes. Alcohol treatment downregulated hepatic DUSP1 expression in wild-type mice. Notably, DUSP1 transgenic ( ) mice showed resistance to alcohol-mediated hepatic dysfunction, as evidenced by decreased AST/ALT activity, improved alcohol metabolism, and suppressed liver fibrosis, inflammation, and oxidative stress. Functional experiments demonstrated that DUSP1 overexpression prevents alcohol-mediated mitochondrial damage in hepatocytes through restoring mitophagy. Accordingly, pharmacological blockade of mitophagy abolished the hepatoprotective actions of DUSP1. Molecular assays showed that DUSP1 binds cytosolic CUL1 and prevents its translocation to the nucleus. Importantly, CUL1 silencing restored the transcription of p62 and Parkin, resulting in mitophagy activation, and sustained mitochondrial integrity and hepatocyte function upon alcohol stress. These results indicate that alcohol-mediated DUSP1 downregulation interrupts DUSP1/CUL1 interaction, leading to CUL1 nuclear translocation and mitophagy inhibition via transcriptional repression of p62 and Parkin. Thus, targeting the DUSP1/CUL1/p62 axis will be a key approach to restore hepatic mitophagy as well as alleviate symptoms of ALD.
除了戒酒，目前尚无有效的方法可以治疗酒精性肝病（ALD），这是酗酒的可怕后果。在这项研究中，我们评估了双特异性磷酸酶-1（DUSP1）和 Cullin-1（CUL1）在 ALD 中的作用，DUSP1 是一种肝脏保护酶，CUL1 是 E3 泛素连接酶复合物的成员，它还具有抑制线粒体基因转录的作用。酒精处理会使野生型小鼠肝脏中的 DUSP1 表达下调。值得注意的是，DUSP1 转基因（）小鼠对酒精介导的肝损伤具有抵抗作用，表现为 AST/ALT 活性降低、酒精代谢改善、肝纤维化、炎症和氧化应激减少。功能实验表明，DUSP1 过表达通过恢复线粒体自噬来防止酒精介导的肝细胞线粒体损伤。相应地，通过药理学阻断线粒体自噬，消除了 DUSP1 的肝保护作用。分子检测表明，DUSP1 与细胞质中的 CUL1 结合并防止其向核内转移。重要的是，沉默 CUL1 可恢复 p62 和 Parkin 的转录，从而激活线粒体自噬，并在酒精应激时维持线粒体完整性和肝细胞功能。这些结果表明，酒精介导的 DUSP1 下调会中断 DUSP1/CUL1 相互作用，导致 CUL1 核内转移和线粒体自噬抑制，这是通过转录抑制 p62 和 Parkin 实现的。因此，靶向 DUSP1/CUL1/p62 轴将是恢复肝线粒体自噬以及缓解 ALD 症状的关键方法。
