Calcitriol alleviates ethanol-induced hepatotoxicity via AMPK/mTOR-mediated autophagy
Calcitriol alleviates ethanol-induced hepatotoxicity via AMPK/mTOR-mediated autophagy
复制标题
骨化三醇通过 AMPK/mTOR 介导的自噬减轻乙醇诱导的肝毒性
DOI：
10.1016/j.abb.2020.108694
复制
发表时间：
2021
影响因子：
3.9
通讯作者：
Yin-xiong Li
中科院分区：
文献类型：
--
作者：
Fang Yuan;Yingying Xu;Kai You;Jiaye Zhang;Fan Yang;Yin-xiong Li
过量的乙醇消耗会导致细胞损伤，导致胎儿酒精综合征和酒精性肝病，这是维生素D （VD）缺乏的常见症状。乙醇引起肝细胞损伤的机制研究取得了很大进展。然而，减少或挽救乙醇引起的肝细胞损伤的干预手段有限。在初步有限筛选过程的基础上，骨化三醇显示出保护肝细胞活力的积极作用。因此，分子基础是值得阐明的。我们发现骨化三醇预处理能显著提高肝细胞活力，减少细胞凋亡和氧化应激，减轻乙醇诱导的肝细胞线粒体形态和膜电位异常。值得注意的是，骨化三醇显著增强了自噬，自噬小体和自噬小体数量增加，LC3B-Ⅱ和ATG5水平上调，p62降解促进。此外，骨化三醇预处理增加了gfp - lc3标记的自噬体与线粒体的共定位，表明骨化三醇有效促进了乙醇诱导的肝细胞线粒体自噬。此外，自噬的抑制减弱了骨化三醇的保护和预防作用。此外，骨化三醇对自噬的影响受AMPK/mTOR信号通路调控，信号转导依赖于维生素D受体（VDR）。综上所述，骨化三醇通过增强自噬来改善乙醇诱导的肝细胞损伤。它可以为偶尔社交饮酒的人提供一种方便的预防和保护肝脏的手段。
Excessive ethanol consumption causes cellular damage, leading to fetal alcohol syndrome and alcohol liver diseases, which are frequently seen with vitamin D (VD) deficiency. A great deal of progress has been achieved in the mechanisms of ethanol-induced hepatocyte damage. However, there are limited intervention means to reduce or rescue hepatocytes damage caused by ethanol. On the basis of our preliminary limited screen process, calcitriol showed a positive effect on protecting hepatocyte viability. Therefore, the molecular basis is worth elucidating. We found that calcitriol pretreatment markedly improved the cell viability, decreased cell apoptosis and oxidative stress and alleviated the abnormal mitochondrial morphology and membrane potential of hepatocytes induced by ethanol. Notably, autophagy was significantly enhanced by calcitriol, as evident by the increasing number of autophagosomes and autolysosomes, upregulated LC3B-Ⅱ and ATG5 levels, and promotion of p62 degradation. Furthermore, calcitriol pretreatment increased the colocalization of GFP-LC3-labeled autophagosomes with mitochondria, suggesting that calcitriol effectively promoted ethanol-induced mitophagy in hepatocytes. In addition, the inhibition of autophagy attenuated the protective and preventive effect of calcitriol. Furthermore, the effect of calcitriol on autophagy was regulated by AMPK/mTOR signaling, and signaling transduction was dependent on the Vitamin D receptor (VDR). In conclusion, calcitriol ameliorates ethanol-induced hepatocyte damage by enhancing autophagy. It may offer a convenient preventive and hepatoprotective mean for people on occasional social drink.