Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway.
Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway.
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DOI：
10.1038/srep29743
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发表时间：
2016-07-12
影响因子：
4.6
通讯作者：
Vasiliou V
中科院分区：
文献类型：
--
作者：
Chen Y;Singh S;Matsumoto A;Manna SK;Abdelmegeed MA;Golla S;Murphy RC;Dong H;Song BJ;Gonzalez FJ;Thompson DC;Vasiliou V
酒精性肝病(ALD)的发病机制尚不清楚。然而，已知氧化应激和相关的谷胱甘肽(GSH)水平下降在ALD中起核心作用。本研究考察了谷胱甘肽缺乏对Gclm基因敲除(KO)小鼠肝脏脂肪变性的影响，该小鼠具有≈15%的正常肝脏谷胱甘肽水平。在长期(6周)喂食含乙醇的流食后，Gclm KO小鼠出人意料地被发现，尽管表现出更高的氧化应激(反映在CYP2E1和蛋白质羰基水平的升高)，但却对脂肪变性具有保护作用。Gclm KO小鼠还表现出肝脏AMP激活蛋白激酶(AMPK)途径和核因子-红系2相关因子2靶基因的结构性激活，表现出乙醇清除增加，肝脏脂质谱改变有利于多不饱和脂肪酸水平增加，与脂肪生成和脂肪酸氧化相关基因表达的协调变化。总之，我们的数据暗示了一种新的机制，通过激活AMPK途径的氧化应激适应性反应来预防肝脏脂肪变性。我们认为，氧化还原激活AMPK可能是预防ALD的一种新的治疗策略。
The pathogenesis of alcoholic liver disease (ALD) is not well established. However, oxidative stress and associated decreases in levels of glutathione (GSH) are known to play a central role in ALD. The present study examines the effect of GSH deficiency on alcohol-induced liver steatosis in Gclm knockout (KO) mice that constitutively have ≈15% normal hepatic levels of GSH. Following chronic (6 week) feeding with an ethanol-containing liquid diet, the Gclm KO mice were unexpectedly found to be protected against steatosis despite showing increased oxidative stress (as reflected in elevated levels of CYP2E1 and protein carbonyls). Gclm KO mice also exhibit constitutive activation of liver AMP-activated protein kinase (AMPK) pathway and nuclear factor-erythroid 2–related factor 2 target genes, and show enhanced ethanol clearance, altered hepatic lipid profiles in favor of increased levels of polyunsaturated fatty acids and concordant changes in expression of genes associated with lipogenesis and fatty acid oxidation. In summary, our data implicate a novel mechanism protecting against liver steatosis via an oxidative stress adaptive response that activates the AMPK pathway. We propose redox activation of the AMPK may represent a new therapeutic strategy for preventing ALD.