Mechanisms regulating autophagy in alcohol-induced liver injury

项目总结： 酒精性肝病(ALD)是全球慢性肝病的主要病因。目前没有成功 ALD的治疗是可用的。酒精性肝损伤的发病机制以肝损害为特征 脂肪变性、炎症和纤维化，可发展为肝硬变和肝癌。细胞可以适应和 通过激活细胞保护机制来应对压力来保护自己，如自噬和 溶酶体和线粒体生物发生。然而，这些保护机制在慢性阻塞性肺疾病后受到损害。 饮酒。慢性酒精损害自噬的潜在分子机制是 不知道。在我们的初步研究中，我们发现慢性和急性酒精狂欢(“高狂欢”) 失活转录因子EB(TFEB)，溶酶体生物发生的主要调节因子，导致受损 溶酶体的生物发生和自噬不足。过表达TFEB可抑制BUT基因敲除 TFEB加重高酒精所致小鼠肝损伤。我们的长期目标是了解 酒精损害肝细胞溶酶体生物发生的分子机制，以确定步骤 在保护途径中，这是酒精性肝病的干预点。这样做的目的是 建议是了解酒精代谢如何激活mTOR导致TFEB失活以及如何 TFEB的遗传和药理激活对酒精性肝损伤具有保护作用。这两个具体的 我们提出的目标是：1)确定酗酒使TFEB失活的机制 2)确定TFEB对酒精性肝损伤的保护作用机制(S 受伤。了解酒精损害TFEB介导的自噬的机制以及 溶酶体和线粒体生物发生最终可能有助于开发新的干预措施 改善酒精性肝病的发病机制。

Project Summary  Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Currently no successful treatment for ALD is available. The pathogenesis of alcohol-induced liver injury is characterized by hepatic steatosis, inflammation, and fibrosis, which can progress to cirrhosis and liver cancer. Cells can adapt and protect themselves in response to stress by activating cellular protective mechanisms such as autophagy and lysosomal and mitochondrial biogenesis. However, these protective mechanisms are impaired after chronic alcohol consumption. The underlying molecular mechanisms by which chronic alcohol impairs autophagy are not known. In our preliminary studies, we found that chronic plus acute alcohol binge (“Gao-binge”) inactivates transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, resulting in impaired lysosomal biogenesis and insufficient autophagy. Overexpression of TFEB protects against but knockdown of TFEB exacerbates Gao-binge alcohol-induced liver injury in mice. Our long-term goal is to understand the molecular mechanisms for how alcohol impairs lysosomal biogenesis in hepatocytes, in order to identify steps in the protective pathway that are points for intervention in alcoholic liver disease. The objective of this proposal is to understand how alcohol metabolism activates mTOR results in TFEB inactivation and how genetic and pharmacological activation of TFEB protects against alcohol-induced liver injury. The two specific aims that we propose are: 1) to determine the mechanisms by which Gao-binge alcohol inactivates TFEB in hepatocytes; and 2) to determine the mechanism(s) by which TFEB protects against alcohol-induced liver injury. Understanding the mechanisms by which alcohol impairs TFEB-mediated autophagy as well as lysosomal and mitochondrial biogenesis may ultimately help to develop novel interventions on the improvement of the pathogenesis of ALD.