Mechanisms regulating autophagy in alcohol-induced liver injury

项目摘要 酒精性肝病（ALD）是世界范围内慢性肝病的主要原因。目前没有成功 ALD的治疗是可行的。酒精性肝损伤的发病机制以肝纤维化为特征， 脂肪变性、炎症和纤维化，其可进展为肝硬化和肝癌。细胞可以适应， 通过激活细胞保护机制（如自噬）来保护自己， 溶酶体和线粒体生物发生。然而，这些保护机制在慢性炎症后受损。 酒精消费。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，我们发现慢性加急性酒精狂欢（“高-狂欢”） 使转录因子EB（TFEB）失活，TFEB是溶酶体生物发生的主要调节因子， 溶酶体生物发生和自噬不足。TFEB的过表达可防止但敲低TFEB。 TFEB可加重酒精所致小鼠肝损伤。我们的长期目标是了解 酒精如何损害肝细胞中溶酶体生物合成的分子机制，以确定步骤 在酒精性肝病的干预点的保护途径。的目的 我们的建议是了解酒精代谢如何激活mTOR导致TFEB失活，以及如何 TFEB的遗传和药理学活化可防止酒精诱导的肝损伤。的两个具体 我们提出的目的是：1）确定高酒精灭活TFEB的机制， 肝细胞;和2）确定TFEB保护免受酒精诱导的肝损伤的机制 损伤了解酒精损害TFEB介导的自噬的机制以及 溶酶体和线粒体生物发生可能最终有助于开发新的干预措施， 改善ALD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.