Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice
Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice
复制标题
Cyanidin-3-O-glucoside 通过促进 PINK1 介导的线粒体自噬改善小鼠非酒精性脂肪肝
DOI：
10.1111/bph.15083
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发表时间：
2020-06-14
影响因子：
7.3
通讯作者：
Liu, Guowen
中科院分区：
文献类型：
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作者：
Li, Xinwei;Shi, Zhen;Liu, Guowen
背景和目的鉴定安全有效的靶向线粒体自噬以消除受损的线粒体的化合物可能是非酒精性脂肪性肝病的有吸引力的治疗策略。在这里，我们研究了矢车菊素-3-O-葡萄糖苷（C3 G）对非酒精性脂肪性肝病（NAFLD）的影响及其机制。实验方法非酒精性脂肪性肝病通过高脂饮食诱导16周。在体内，分别用重组腺病毒和AAV 8来过表达和敲低PTEN诱导的激酶1（PINK 1）。以AML-12和HepG 2细胞为研究对象，探讨其作用机制。C3 G给药抑制肝脏氧化应激、NLR家族pyrin结构域3（NLRP 3）炎性小体活化和脂肪变性，并改善NAFLD小鼠的全身葡萄糖代谢。在棕榈酸处理的AML-12细胞和NAFLD患者的肝细胞中也观察到C3 G的这些作用。机制研究表明，C3 G增加PINK 1/Parkin表达和线粒体定位，并促进PINK 1介导的线粒体自噬，以清除受损的线粒体。敲低肝脏PINK 1可消除C3 G的线粒体自噬诱导作用，从而减弱C3 G对氧化应激、NLRP 3炎性小体激活、肝脏脂肪变性和葡萄糖代谢的有益作用。结论和意义这些结果表明，PINK 1介导的线粒体自噬在C3 G缓解NAFLD的能力中起着至关重要的作用，并表明C3 G可能是治疗NAFLD的潜在候选药物。
Background and Purpose Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism. Experimental Approach Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks.In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study. Key Results C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism. Conclusion and Implications These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment.