Mechanisms regulating autophagy in alcohol-induced liver injury

酒精性肝损伤中自噬的调节机制

基本信息

批准号：
10468416
负责人：
Wen-Xing Ding
金额：
$ 34.84万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10468416
关键词：
Acetaldehyde Acids Acute Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Attenuated Autophagocytosis Biogenesis Catabolic Process Cells Cessation of life Chronic Cirrhosis Consumption Data Development Ethanol Ethanol Metabolism FRAP1 gene Fatty Liver Fibrosis Genes Genetic Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Hepatic Hepatocyte High Fat Diet Human Hydrolase Impairment Inflammation Instruction Intervention Knock-in Mouse Knock-out Knockout Mice Liver Lysosomes Malignant neoplasm of liver Mediating Mitochondria Modeling Molecular Monitor Morbidity - disease rate Mus Nuclear Translocation Organelles Outcome PPAR gamma Pathogenesis Pathway interactions Pattern Pharmacology Phosphorylation Prevention Principal Investigator Proteins Protocols documentation Publishing Raptors Recovery Role Signal Transduction Stress Testing Therapeutic Intervention Transcriptional Activation activating transcription factor aldehyde dehydrogenases chronic alcohol ingestion chronic liver disease fatty acid oxidation feeding gain of function improved knock-down liver inflammation liver injury mortality mouse model novel novel therapeutic intervention overexpression problem drinker response targeted treatment transcription factor

Acetaldehyde Acids Acute Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Attenuated Autophagocytosis Biogenesis Catabolic Process Cells Cessation of life Chronic Cirrhosis Consumption Data Development Ethanol Ethanol Metabolism FRAP1 gene Fatty Liver Fibrosis Genes Genetic Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Hepatic Hepatocyte High Fat Diet Human Hydrolase Impairment Inflammation Instruction Intervention Knock-in Mouse Knock-out Knockout Mice Liver Lysosomes Malignant neoplasm of liver Mediating Mitochondria Modeling Molecular Monitor Morbidity - disease rate Mus Nuclear Translocation Organelles Outcome PPAR gamma Pathogenesis Pathway interactions Pattern Pharmacology Phosphorylation Prevention Principal Investigator Proteins Protocols documentation Publishing Raptors Recovery Role Signal Transduction Stress Testing Therapeutic Intervention Transcriptional Activation activating transcription factor aldehyde dehydrogenases chronic alcohol ingestion chronic liver disease fatty acid oxidation feeding gain of function improved knock-down liver inflammation liver injury mortality mouse model novel novel therapeutic intervention overexpression problem drinker response targeted treatment transcription factor

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项目摘要

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.

酒精性肝病（ALD）是全球慢性肝病的主要原因。目前没有成功可以接受ALD的治疗。酒精引起的肝损伤的发病机理的特征是肝脂肪变性，感染和纤维化，可以发展为肝硬化和肝癌。细胞可以通过激活细胞保护机制（例如自噬，溶酶体和线粒体生物发生。但是，这些受保护的机制是长期饮酒后受损。慢性的基本分子机制酒精会损害自噬，尚不清楚。在我们的初步研究中，我们发现慢性加急性酒精暴饮（“ Gao-binge”）使转录因子EB（TFEB）灭活，溶酶体的主调节剂生物发生，导致溶酶体生物发生受损和自噬不足。过表达 TFEB可以防止TFEB外脱甲酸盐抑制Gao-Binginge酒精诱导的肝损伤老鼠。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中的生物发生，以识别受保护途径中的步骤干预酒精性肝病。该提议的目的是了解酒精代谢激活MTOR导致TFEB失活以及遗传和药物激活如何 TFEB可预防酒精引起的肝损伤。我们提出的两个具体目标是：1）确定Gao-Binge酒精使TFEB在肝细胞中灭活的机制；和2）到确定TFEB防止酒精诱导的肝损伤的机制。理解酒精会损害TFEB介导的自噬以及溶酶体和线粒体生物发生可能最终有助于发展有关改进的新干预措施 ALD的发病机理。相关性（请参阅说明）：酒精滥用和消费是酒精性肝病的主要原因，其发病率高和死亡率和没有特定治疗方法。饮酒会损害溶酶体生物发生结果在自噬和酒精脂肪变性和肝损伤的情况下。阐明分子机制激活TFEB如何改善酒精受损的溶酶体生物发生和自噬将有助于开发用于治疗酒精性肝病的新型治疗策略。