Chronic alcohol consumption is a well-known risk factor for liver disease. Progression of alcohol-induced liver disease (ALD) is a multifactorial process that involves a number of genetic, nutritional and environmental factors. Experimental and clinical studies increasingly show that oxidative damage induced by ethanol contributes in many ways to the pathogenesis of alcohol hepatoxicity. Oxidative stress appears to activate AMP-activated protein kinase (AMPK) signaling system, which has emerged in recent years as a kinase that controls the redox-state and mitochondrial function. This review focuses on the most recent insights concerning the activation of AMPK by reactive oxygen species (ROS), and describes recent evidences supporting the hypothesis that AMPK signaling pathways play an important role in promoting cell viability under conditions of oxidative stress, such as during alcohol exposure. We suggest that AMPK activation by ROS can promote cell survival by inducing autophagy, mitochondrial biogenesis and expression of genes involved in antioxidant defense. Hence, increased intracellular concentrations of ROS may represent a general mechanism for enhancement of AMPK-mediated cellular adaptation, including maintenance of redox homeostasis. On the other hand, AMPK inhibition in the liver by ethanol appears to play a key role in the development of steatosis induced by chronic alcohol consumption. Although more studies are needed to assess the functions of AMPK during oxidative stress, AMPK may be a possible therapeutic target in the particular case of alcohol-induced liver disease.

译文

长期饮酒是众所周知的肝脏疾病的危险因素。酒精引起的肝病 (ALD) 的进展是一个多因素过程,涉及许多遗传,营养和环境因素。实验和临床研究越来越多地表明,乙醇诱导的氧化损伤在许多方面参与了酒精肝毒性的发病机制。氧化应激似乎激活了AMP激活的蛋白激酶 (AMPK) 信号系统,近年来,该系统已作为控制氧化还原状态和线粒体功能的激酶出现。这篇综述着重于有关活性氧 (ROS) 激活AMPK的最新见解,并描述了支持以下假设的最新证据: AMPK信号通路在氧化应激条件下 (例如酒精暴露期间) 在促进细胞活力中起重要作用。我们认为,ROS激活AMPK可以通过诱导自噬,线粒体生物发生和参与抗氧化防御的基因表达来促进细胞存活。因此,细胞内ROS浓度的增加可能代表了增强AMPK介导的细胞适应性的一般机制,包括维持氧化还原稳态。另一方面,乙醇对肝脏中的AMPK抑制似乎在慢性饮酒引起的脂肪变性的发展中起关键作用。尽管需要更多的研究来评估氧化应激期间AMPK的功能,但AMPK可能是酒精引起的肝病的特定情况下的治疗靶标。

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