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

描述(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，可导致终末期肝硬变和多种并发症。乙醇具有非常广泛的生物学效应，影响多种细胞过程。虽然对酒精性肝损伤的发病机制的了解已经取得了重大进展，但关于细胞防御酒精的有害影响的研究还很少。我们最近发现，急性乙醇处理可诱导巨噬细胞自噬，对乙醇诱导的细胞凋亡和肝损伤有明显的保护作用。巨自噬是一种进化保守的细胞内降解机制，参与多种生物学活动，并参与多种疾病的发病机制。因此，了解巨自噬如何以及为什么可以抵消乙醇对肝脏的毒性将是非常重要的，这将有助于进一步了解ALD的发病机制，更重要的是，可以找到治疗该疾病的新方法。我们发现，乙醇诱导的自噬的特征是对受损的线粒体和脂滴具有选择性，而不是一般蛋白质。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。本项目的目的1将研究乙醇条件下自噬小体识别受损线粒体和脂滴的机制，以及在长期乙醇处理过程中自噬的动力学，以确定自噬功能是否以及如何在这一过程中发生变化，从而为制定可能的治疗策略以增强自噬功能提供重要信息。该项目的目标2将检验以下假设：自噬通过移除受损的线粒体和降低细胞总脂质含量来减少乙醇诱导的细胞死亡和肝损伤，最终导致ROS的产生减少，脂质过氧化， 以及内质网压力。我们预计，这项研究将对自噬如何在乙醇诱导的发病机制中发挥作用产生重要的和系统的发现。自噬是否以及如何影响ALD的进展这一问题是新的、关键的，但研究还不够充分，尽管 对疾病(ALD)和机制(肝脏自噬)的重要性的广泛认识。因此，该项目可能为开发治疗ALD的新方法提供重要信息。

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.