2-Methoxyestradiol protects against ischemia/reperfusion injury in alcoholic fatty liver by enhancing sirtuin 1-mediated autophagy
2-Methoxyestradiol protects against ischemia/reperfusion injury in alcoholic fatty liver by enhancing sirtuin 1-mediated autophagy
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DOI：
10.1016/j.bcp.2017.02.008
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发表时间：
2017-05-01
影响因子：
5.8
通讯作者：
Lee, Sun-Mee
中科院分区：
文献类型：
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作者：
Cho, Hong-Ik;Seo, Min-Jong;Lee, Sun-Mee
酒精性脂肪肝（AFL）易发生缺血/再灌注（I/R）损伤，反应为炎症和广泛的肝细胞损伤。自噬维持细胞内稳态，调节炎症和脂质代谢。2-甲氧基yestradiol （2-ME2）是雌二醇的内源性代谢物，具有抗氧化和抗炎特性。本研究探讨了2-ME2对AFL肝I/R的细胞保护机制，重点关注自噬信号。C57BL/6小鼠分别饲喂乙醇诱导AFL （ED）和对照饲料（CD） 6周，缺血60 min，再灌注5 h。缺血前12 h、再灌注前10 min给予2-ME2 (15 mg/kg, i.p)，再灌注前30 min给予sirtinol （sirtuin 1 （SIRT1）抑制剂，10 mg/kg, i.p）。再灌注后，ED动物血清转氨酶活性和促炎细胞因子水平均高于CD动物，组织学变化更为严重。这些改变被2-ME2减弱。在ED I/R组，自噬和有丝自噬明显受损，表现为肝脏微管相关蛋白1轻链3 II和parkin蛋白表达水平降低，p62蛋白表达升高，2-ME2使其减弱。在ED I/R动物肝脏中，Atgl - 2-5复合物、Atg3、Atg7、溶酶体相关膜蛋白2和Rab7蛋白的表达水平显著降低，2- me2对其有抑制作用。在ED I/R组，SIRT1蛋白表达水平及其催化活性显著降低，并被2-ME2减弱。Sirtinol逆转了2-ME2对自噬的刺激作用。我们的研究结果表明，2-ME2通过激活sirt1介导的自噬信号，改善I/ r诱导的AFL肝细胞损伤。(C) 2017爱思唯尔公司版权所有。
Alcoholic fatty liver (AFL) is susceptible to ischemia/reperfusion (I/R) injury, responding with inflammation and extensive hepatocellular damage. Autophagy maintains cellular homeostasis and regulates inflammation and lipid metabolism. 2-Methoxyestradiol (2-ME2), an endogenous metabolite of estradiol, exhibits antioxidant and anti-inflammatory properties. This study examined the cytoprotective mechanisms of 2-ME2 on hepatic I/R in AFL, focusing on autophagy signaling. C57BL/6 mice were fed an ethanol diet (ED) to induce AFL, or a control diet (CD) for 6 weeks, and then subjected to 60 min of ischemia and 5 h of reperfusion. 2-ME2 (15 mg/kg, i.p.) was administered 12 h before ischemia and 10 min before reperfusion, and sirtinol (sirtuin 1 (SIRT1) inhibitor, 10 mg/kg, i.p.) was administered 30 min before reperfusion. After reperfusion, ED animals showed higher serum aminotransferase activities and proinflammatory cytokine levels, and more severe histological changes compared with CD animals. These alterations were attenuated by 2-ME2. In the ED I/R group, autophagy and mitophagy were significantly impaired, as indicated by decreased hepatic levels of microtubule-associated protein 1 light chain 3 II and parkin protein expression, and increased p62 protein expression, which were attenuated by 2-ME2. The hepatic levels of Atgl 2-5 complex, Atg3, Atg7, lysosomal-associated membrane protein 2 and Rab7 protein expression significantly decreased in ED I/R animals, which were attenuated by 2-ME2. In the ED I/R group, the level of SIRT1 protein expression and its catalytic activity significantly decreased, which were attenuated by 2-ME2. Sirtinol reversed the stimulatory effect of 2-ME2 on autophagy. Our findings suggest that 2-ME2 ameliorates I/R-induced hepatocellular damage in AFL through activating SIRT1-mediated autophagy signaling. (C) 2017 Elsevier Inc. All rights reserved.