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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：
10612977
负责人：
Wen-Xing Ding
金额：
$ 34.88万
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/10612977
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 Pattern Phosphorylation Prevention Principal Investigator Proteins Protocols documentation Publishing 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 loss of function mortality mouse model novel novel therapeutic intervention overexpression pharmacologic problem drinker programs protective pathway response targeted treatment transcription factor

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的特点是，肝脂肪变性、炎症和纤维化，其可进展为肝硬化和肝癌。细胞可以通过激活细胞保护机制来适应和保护自己，自噬以及溶酶体和线粒体生物发生。然而，这些保护机制长期饮酒后受损。慢性炎症的潜在分子机制酒精损害自噬是未知的。在我们的初步研究中，我们发现慢性加急性酒精狂欢（“Gao-binge”）使转录因子EB（TFEB）失活，转录因子EB是溶酶体的主要调节因子，生物发生，导致溶酶体生物发生受损和自噬不足。过表达 TFEB对高酒精诱导的肝损伤有保护作用，但TFEB的敲低会加重高酒精诱导的肝损伤。小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，以确定保护途径中的步骤，酒精性肝病的治疗这项提案的目的是了解酒精如何代谢激活mTOR导致TFEB失活，以及遗传和药理学激活如何 TFEB可防止酒精引起的肝损伤。我们提出的两个具体目标是：1）确定高酒精灭活肝细胞中TFEB的机制; 2）确定TFEB保护免受酒精诱导的肝损伤的机制。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可能最终有助于开发新的干预措施， ALD的发病机制相关性（参见说明）：酒精滥用和消费是酒精性肝病的主要原因，酒精性肝病的发病率高，死亡率和没有具体的治疗方法。饮酒损害溶酶体生物发生结果自噬不足酒精性脂肪变性和肝损伤阐明了如何激活TFEB以改善酒精损害的溶酶体生物发生和自噬将有助于开发治疗酒精性肝病的新治疗策略。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of p62/SQSTM1 in liver physiology and pathogenesis.

DOI：
10.1177/1535370213489446
发表时间：
2013-05
期刊：
Experimental biology and medicine (Maywood, N.J.)
影响因子：
0
作者：
Manley S;Williams JA;Ding WX
通讯作者：
Ding WX

Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.

晚年接触酒精不会加剧小鼠空间记忆和大脑 TFEB 活动的年龄依赖性下降。

DOI：
10.1101/2024.02.23.581774
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Chen,Hao;Hinz,Kaitlyn;Zhang,Chen;Rodriguez,Yssa;Williams,ShaNeisha;Niu,Mengwei;Ma,Xiaowen;Chao,Xiaojuan;Frazier,AlexandriaL;McCarson,KennethE;Wang,Xiaowan;Peng,Zheyun;Liu,Wanqing;Ni,Hong-Min;Zhang,Jianhua;Swerdlow,Russell
通讯作者：
Swerdlow,Russell

Reply: Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation.

答复：肝脏 DRP1 缺失会诱导巨线粒体和线粒体适应不良，从而加剧酒精性肝炎。

DOI：
10.1097/hep.0000000000000541
发表时间：
2023
期刊：
Hepatology (Baltimore, Md.)
影响因子：
0
作者：
Ma,Xiaowen;Ding,Wen-Xing
通讯作者：
Ding,Wen-Xing

Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.

NRF2促进肝自噬有缺陷的小鼠纤维化和肿瘤发生的发展。

DOI：
10.1016/j.jhep.2014.04.043
发表时间：
2014-09
期刊：
JOURNAL OF HEPATOLOGY
影响因子：
25.7
作者：
Ni, Hong-Min;Woolbright, Benjamin L.;Williams, Jessica;Copple, Bryan;Cui, Wei;Luyendyk, James P.;Jaeschke, Hartmut;Ding, Wen-Xing
通讯作者：
Ding, Wen-Xing

Caveats to link in vitro mechanistic mitophagy studies to the pathogenesis of non-alcoholic steatohepatitis.

将体外机制线粒体自噬研究与非酒精性脂肪性肝炎的发病机制联系起来的注意事项。