Mechanisms regulating autophagy in alcohol-induced liver injury

描述(申请人提供)：自噬是一种遗传编程、进化保守的过程，它降解长寿的细胞蛋白和受损的细胞器，包括线粒体，作为应对压力的关键细胞生存机制。我们最近报道了乙醇诱导自噬，从而减少乙醇诱导的肝损伤(Ding等人，2010a)。这是一个重要的发现，因为在美国，酗酒是肝病的主要原因，也是一个主要的健康问题。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移除受损的线粒体来保护自己。因此，调节自噬过程可能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可能性将是有限的。我们的初步研究表明，叉头转录因子FOXO3a可能在乙醇诱导的自噬中发挥重要作用。因此，中心假设是乙醇通过激活FOXO3a诱导自噬，而自噬去除乙醇诱导的受损线粒体是预防乙醇诱导的肝脏发病的关键。为了验证我们的假设，我们提出了三个具体的目标：1)确定乙醇激活肝细胞中FOXO3a的机制，2)确定乙醇激活的FOXO3a如何诱导肝细胞自噬，以及3)确定去除受损的线粒体以保护其免受乙醇诱导的肝毒性的机制。在这项申请中提出的研究是创新的，其概念是乙醇可以激活自噬，作为一种保护机制，以抵御其对肝脏的已知有害影响。此外，我们将利用新的遗传动物模型，如GFP-LC3转基因和ATG5肝脏特异性基因敲除小鼠，专门研究自噬在酒精性肝损伤中的作用。此外，重点介绍了FOXO3a介导的自噬途径在酒精性肝病中的作用，这方面的研究尚未见报道。这项研究具有重要意义，因为这项研究的结果将有助于理解自噬在酒精诱导的肝脏发病中的机制和作用。最终，这些知识有可能为通过调节自噬来治疗酒精性肝脏疾病提供新的治疗方法。

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.