Mechanism and role of selective autophagy in ethanol-induced liver injury

描述（由申请人提供）：酒精性肝病（ALD）以脂肪变性、炎症和纤维化为特征，可导致终末期肝硬化和多种并发症。乙醇具有非常广泛的生物效应，影响多种细胞过程。虽然对乙醇诱导肝损伤的发病机制的理解已经取得了重大进展，但对细胞防御乙醇有害影响的了解还很多。我们最近发现急性乙醇处理可诱导巨噬，并对乙醇诱导的细胞凋亡和肝损伤具有显著的保护作用。巨噬是一种进化保守的细胞内降解机制，参与多种生物活性和许多疾病的发病机制。因此，了解巨噬如何以及为什么可以抵消肝脏中乙醇的毒性是很重要的，这可能会导致进一步了解ALD的发病机制，更重要的是，治疗这种疾病的新方法。我们发现乙醇诱导的自噬的特点是其对受损线粒体和脂滴的选择性，而不是对一般蛋白质的选择性。因此，我们假设这一特征一定与自噬如何影响乙醇诱导的毒性有关。本项目目的1将研究乙醇条件下自噬体对受损线粒体和脂滴的识别机制，以及长时间乙醇处理过程中自噬的动态变化，以确定自噬功能在此过程中是否以及如何发生变化，从而为制定可能的治疗策略提供重要信息，以增强自噬功能。该项目的目标2将检验自噬通过去除受损线粒体和降低细胞总脂质含量，最终减少ROS生成，脂质过氧化，

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is characterized by steatosis, inflammation and fibrosis, which can lead to end stage cirrhosis and multiple complications. Ethanol has very broad biological effects affecting multiple cellular processes. While significant progresses have been made regarding the understanding of the pathogenesis of ethanol induced liver injury, much has yet to be learnt about the cellular defense against the detrimental effects of ethanol. We recently find that macroautophagy is induced by acute ethanol treatment and has significant protective effects against ethanol-induced apoptosis and liver injury. Macroautophagy is an evolutionarily conserved intracellular degradation mechanism involved in diverse biological activities and in the pathogenesis of many diseases. It would thus be important to understand how and why macroautophagy can counteract the toxicity of ethanol in the liver, which could lead to a further understanding of the pathogenesis of ALD, and, more importantly, novel approaches to treat the disease. We have found that ethanol-induced autophagy is characterized by its selectivity toward damaged mitochondria and lipid droplets, but not general proteins. We thus hypothesize that this feature must be related to how autophagy affects ethanol-induced toxicity. Aim 1 of this project will investigate the mechanisms involved in the recognition of the damaged mitochondria and lipid droplets by the autophagosome in the ethanol conditions, and the dynamics of autophagy during a prolonged ethanol treatment to determine whether and how the function of autophagy may change during this course, thus providing important information for forge a possible therapeutic strategy to enhancing autophagy function. Aim 2 of this project will examine the hypothesis that autophagy reduces ethanol-induced cell death and liver injury by removing damaged mitochondria and reducing total cellular lipid content, culminating in decreased ROS generation, lipid peroxidation, and ER stress. We anticipate that this study will result in important and systemic findings of how autophagy may function in ethanol-induced pathogenesis. The subject of whether and how autophagy may affect the progression of ALD is novel, critical, but insufficiently studied, despite the wide recognition of the importance of both the disease (ALD) and the mechanism (autophagy in the liver). This project could thus yield important information for the development of a novel approach toward the treatment of ALD.