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首页> 外文期刊>Biochemical Pharmacology >2-Methoxyestradiol protects against ischemia/reperfusion injury in alcoholic fatty liver by enhancing sirtuin 1-mediated autophagy
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2-Methoxyestradiol protects against ischemia/reperfusion injury in alcoholic fatty liver by enhancing sirtuin 1-mediated autophagy

机译：通过增强SIRTUIN 1介导的自噬，通过增强SIRTUIN 1介导的血液脂肪肝中的缺血/再灌注损伤来保护2-甲氧基雌二醇

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摘要

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.
机译：酒精脂肪肝（AFL）易于缺血/再灌注（I / R）损伤，伴有炎症和广泛的肝细胞损伤。自噬维持细胞稳态并调节炎症和脂质代谢。 2-甲氧基雌二醇（2-Me2），雌二醇的内源代谢素，表现出抗氧化剂和抗炎特性。本研究检测了2-Me2在AFL中的肝脏I / R的细胞保护机制，重点是自噬信号传导。将C57BL / 6小鼠加入乙醇饮食（ED）以诱导AFL，或对照饮食（CD）6周，然后进行60分钟的缺血和5小时再灌注。在再灌注前10分钟，在再灌注前10分钟，在再灌注前30分钟施用2-Me2（15mg / kg，i.p.）和10分钟的10分钟给药。再灌注后，ED动物显示出更高的血清氨基转移酶活性和促炎细胞因子水平，与CD动物相比更严重的组织学变化。这些改变通过2-ME2衰减。在ED I / R组中，自噬和水道显着损害，如微管相关蛋白1轻链3 II和Parkin蛋白表达的肝脏水平降低，以及增加的P62蛋白表达，其衰减为2-Me2。在ED I / R动物中，ATG 2-5络合物，ATG3，ATG7，溶酶体相关膜蛋白2和RAB7蛋白表达的肝脏水平显着降低，其衰减2-Me2。在ED I / R组中，SIRT1蛋白表达水平及其催化活性显着降低，其衰减2-Me2。 Sirtinol反转2-Me2对自噬的刺激作用。我们的研究结果表明，通过激活SIRT1介导的自噬信号传导，2-Me2改善了AFL中的I / R诱导的肝细胞损伤。 （c）2017年Elsevier Inc.保留所有权利。

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