Hepatic SIRT3 Upregulation in Response to Chronic Alcohol Consumption Contributes to Alcoholic Liver Disease in Mice
Hepatic SIRT3 Upregulation in Response to Chronic Alcohol Consumption Contributes to Alcoholic Liver Disease in Mice
复制标题
慢性饮酒引起的肝脏 SIRT3 上调导致小鼠酒精性肝病
DOI：
10.3389/fphys.2019.01042
复制
发表时间：
2019-08-13
影响因子：
4
通讯作者：
Li, Songtao
中科院分区：
文献类型：
--
作者：
Ma, Yue;Chai, Hui;Li, Songtao
研究背景酒精性肝病（alcoholicliverdisease，ALD）是一种因长期过量饮酒而引起的慢性肝病。ALD的发病机制复杂，临床上尚无有效的治疗方法。SIRT 3是主要位于线粒体内的NAD+依赖性脱乙酰酶，并且关于慢性酒精暴露对肝脏SIRT 3表达的影响的报道很少。本研究旨在探讨慢性饮酒对肝脏SIRT 3表达的影响及其在酒精性肝损伤中的作用。方法采用Lieber-DeCarli小鼠酒精性肝损伤模型，分析SIRT 3的调控及肝脏特异性敲低SIRT 3对酒精性肝损伤的影响。以HepG 2和AML 12肝细胞为研究对象，探讨SIRT 3在酒精诱导的肝细胞毒性中的生物学功能及其可能机制。结果慢性酒精暴露导致肝脏SIRT 3表达上调，肝脏特异性SIRT 3敲低可减轻酒精性喂养诱导的肝损伤和脂质蓄积，这与自噬诱导的改善有关。此外，自噬诱导有助于SIRT 3敲低对乙醇诱导的肝细胞死亡的细胞保护作用。结论慢性酒精暴露后肝脏SIRT 3表达上调，SIRT 3基因敲低，诱导自噬激活，进一步减轻酒精性肝损伤，这是一种新的机制。
Background Alcoholic liver disease (ALD) is a type of chronic liver disease caused by chronic ethanol overconsumption. The pathogenesis of ALD is complex and there is no effective clinical treatment thus far. SIRT3 is an NAD+-dependent deacetylase primarily located inside mitochondria, and reports on the effect of chronic alcohol exposure on liver SIRT3 expression are scarce. This study aims to investigate the effect of chronic alcohol consumption on hepatic SIRT3 expression and its role in alcoholic-induced liver injury. Methods Using the Lieber-DeCarli mouse model of ALD, we analyzed the regulation of SIRT3 and the effect of liver-specific knocking-down of SIRT3 on alcohol-induced liver injury. HepG2 and AML12 hepatocytes were employed to detect the biological function of SIRT3 on alcohol-induced hepatic cytotoxicity and its potential mechanism. Results Chronic alcohol exposure led to hepatic SIRT3 upregulation and liver-specific SIRT3 knockdown alleviated alcoholic feeding-induced liver injury and lipid accumulation, which is associated with improved autophagy induction. In addition, autophagy induction contributed to the cytoprotective effect of SIRT3 knockdown on ethanol-induced hepatocyte cell death. Conclusion In summary, our data suggest that hepatic SIRT3 upregulation in response to chronic alcohol exposure and liver-specific SIRT3 knockdown, induced autophagy activation further alleviating alcoholic-induced liver injury, which represents a novel mechanism in this process.