Mechanisms regulating autophagy in alcohol-induced liver injury

描述（由申请人提供）：自噬是一种遗传编程的、进化上保守的过程，其降解长寿命的细胞蛋白和受损的细胞器，包括线粒体，作为响应应激的关键细胞存活机制。我们最近报道了乙醇诱导自噬，其减少乙醇诱导的肝损伤（Ding等人，2010年a）。这是一个重要的发现，因为酒精滥用是肝脏疾病的主要原因，也是美国的一个主要健康问题。氧化应激和线粒体损伤在酒精性肝毒性中起重要作用。细胞可以通过自噬等机制清除受损的线粒体来保护自己。因此，调节自噬过程可以为酒精性肝病提供新的治疗方法。然而，乙醇诱导自噬的机制以及自噬如何保护乙醇诱导的肝脏发病机制尚不清楚。如果没有这样的理解，最终使用自噬治疗酒精相关肝病的潜力将受到限制。我们的初步研究表明，叉头转录因子FoxO 3a可能在乙醇诱导的自噬中起主要作用。因此，中心假设是乙醇通过激活FoxO 3a诱导自噬，并且乙醇诱导的受损线粒体的自噬去除对于防止乙醇诱导的肝脏发病至关重要。为了检验我们的假设，提出了三个具体的目标：1）确定乙醇激活肝细胞中FoxO 3a的机制，2）确定乙醇激活的FoxO 3a如何诱导肝细胞自噬，3）确定去除受损线粒体保护乙醇诱导的肝毒性的机制。本申请中提出的研究在乙醇可以激活自噬作为其对肝脏已知有害影响的保护机制的概念上是创新的。此外，我们将利用新型遗传动物模型，如GFP-LC 3转基因和Atg 5肝脏特异性敲除小鼠，专门研究自噬在酒精诱导的肝损伤中的作用。此外，它集中在FoxO 3a介导的自噬途径在酒精性肝病中的作用，尚未研究。这项研究具有重要意义，因为这项研究的结果将有助于了解自噬在酒精诱导的肝脏发病机制中的作用和机制。最终，这些知识有可能提供新的治疗方法，通过调节自噬来治疗酒精性肝发病机制。

DESCRIPTION (provided by applicant): Autophagy is a genetically programmed, evolutionarily conserved process that degrades long-lived cellular proteins and damaged organelles, including mitochondria, as a critical cell survival mechanism in response to stress. We recently reported that ethanol induces autophagy, which reduces ethanol-induced liver injury (Ding et al., 2010a). This is an important finding because alcohol abuse is a major cause of liver disease and a major health problem in the United States. Oxidative stress and mitochondrial damage play important roles in alcohol-induced hepatotoxicity. Cells may protect themselves by removing damaged mitochondria by mechanisms such as autophagy. Therefore modulating the autophagy process could offer new therapeutic treatments for alcoholic liver diseases. However, the mechanisms by which ethanol induces autophagy and how autophagy protects against ethanol-induced liver pathogenesis are not clear. Without such understanding, the potential to ultimately use autophagy in the treatment of alcohol-related liver disease will be limited. Our preliminary studies suggest that the forkhead transcription factor FoxO3a could play a major role in ethanol- induced autophagy. Therefore, the central hypothesis is that ethanol induces autophagy by activating FoxO3a, and autophagic removal of ethanol-induced damaged mitochondria is crucial to protect against ethanol- induced liver pathogenesis. To examine our hypothesis, three specific aims are proposed: 1) determine the mechanisms by which ethanol activates FoxO3a in hepatocytes, 2) determine how ethanol-activated FoxO3a induces autophagy in hepatocytes, and 3) determine the mechanisms by which removal of damaged mitochondria protects against ethanol-induced hepatotoxicity. The research proposed in this application is innovative in the concept that ethanol can activate autophagy as a protective mechanism against its known detrimental effects on the liver. Moreover, we will utilize novel genetic animal models such as GFP-LC3 transgenic and Atg5 liver-specific knockout mice to specifically study the role of autophagy in alcohol-induced liver injury. Furthermore, it focuses on the role of FoxO3a-mediated autophagy pathway in alcoholic liver disease, which has not been studied. The proposed research is significant because the results from this study will lead to the understanding of mechanisms and roles of autophagy in alcohol-induced liver pathogenesis. Ultimately, such knowledge has the potential of offering novel therapeutic approaches for treating alcoholic liver pathogenesis by modulating autophagy.