Mechanisms regulating autophagy in alcohol-induced liver injury

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具有以下特点 肝脏脂肪变性、炎症和纤维化，可发展为肝硬变和肝癌。细胞可以 通过激活细胞保护机制来适应和保护自己以应对压力 自噬、溶酶体和线粒体的生物发生。然而，这些保护机制是 长期饮酒后身体受损。慢性阻塞性肺疾病的潜在分子机制 酒精对自噬的损害尚不清楚。在我们的初步研究中，我们发现慢性加上急性 酗酒使溶酶体的主要调节因子转录因子EB(TFEB)失活 生物发生，导致溶酶体生物发生受损和自噬不足。过度表达 TFEB对酒精性肝损伤有保护作用，但TFEB基因敲除可加重酒精性肝损伤 老鼠。我们的长期目标是了解酒精如何损害溶酶体的分子机制。 肝细胞的生物发生，以确定保护途径中的哪些步骤是 酒精性肝病的干预。这项提议的目标是了解酒精如何 代谢激活mTOR导致TFEB失活以及遗传和药物激活如何 TFEB对酒精性肝损伤有保护作用。我们提出的两个具体目标是：1) 确定豪饮酒精灭活肝细胞中TFEB的机制；以及2) 确定TFEB对酒精性肝损伤的保护机制(S)。理解 酒精损害TFEB介导的自噬以及溶酶体和 线粒体生物发生最终可能有助于开发新的干预措施来改善 ALD的发病机制。 相关性(请参阅说明)： 酗酒和饮酒是酒精性肝病的主要原因，酒精性肝病的发病率和 死亡，而且没有特别的治疗方法可用。饮酒损害溶酶体生物发生的结果 自噬不足、酒精性脂肪变性和肝脏损伤。阐明黄曲霉毒素的分子机制 激活TFEB改善酒精损伤的溶酶体生物发生和自噬的作用 开发治疗酒精性肝病的新治疗策略。

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. RELEVANCE (See instructions): Alcohol abuse and consumption are major causes of alcoholic liver disease, which has high morbidity and mortality and no specific treatment is available. Alcohol consumption impairs lysosomal biogenesis results in insufficient autophagy and alcoholic steatosis and liver injury. Elucidating the molecular mechanisms of how activating TFEB to improve lysosomal biogenesis and autophagy that are impaired by alcohol will help to develop novel therapeutic strategies for treating alcoholic liver disease.