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Synergy of lipolysis and lipophagy in alcoholic liver disease

脂肪分解和脂肪吞噬在酒精性肝病中的协同作用

基本信息

批准号：
10489818
负责人：
Micah Schott
金额：
$ 24.9万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10489818
关键词：
Acid Lipase Address Adipocytes Adipose tissue Adrenergic Agents Advisory Committees Affect Alcohol consumption Alcoholic Fatty Liver Alcoholic Liver Diseases Alcoholic beverage heavy drinker Alcohols Animal Model Autophagocytosis Autophagosome Biochemistry Bioinformatics Biological Biology Catabolism Cells Cholesterol Cirrhosis Clinic Committee Members Complement Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Progression Elderly Endosomes Environment Enzymes Ethanol Event Fatty Liver Fibrosis Future Gastroenterology Genetic Transcription Goals Hepatic Hepatitis Hepatocyte Hepatology Hydrolysis Impairment Knowledge Lead Lipase Lipids Lipolysis Liver Lysosomes Malignant Neoplasms Manuscripts Mass Spectrum Analysis Mediating Membrane Mentors Microscopy Multivesicular Body Obesity Organelles Outcome Pathway interactions Peripheral Pharmacology Pharmacotherapy Phase Phosphotransferases Positioning Attribute Process Progressive Disease Protein Kinase Protein phosphatase Proteins Proteome Proteomics Publishing Regulation Research Rodent Model Role Schools Signal Transduction Sorting - Cell Movement Surface Testing Training Triglycerides Vesicle Work base cell type chronic alcohol ingestion combat comparative in vivo insight liver injury multidisciplinary novel problem drinker protein activation public health relevance receptor recruit response sterol esterase synergism trafficking transcription factor uptake

项目摘要

Project Summary/Abstract My long-term objective is to discover new cellular mechanisms that contribute to alcoholic liver disease (ALD), a progressive disease leading to non-reversible stages that can be fatal. One of the early and reversible precursors of ALD is alcoholic steatosis, in which large triglyceride and cholesterol-rich lipid droplets (LDs) accumulate within hepatocytes, the main functional cell type of the liver. While LDs are believed to be central to the progression of ALD, the cellular mechanisms whereby alcohol disrupts the breakdown of these organelles are poorly understood. To address this important gap in knowledge, this proposal will define the synergy between two seemingly-distinct processes of lipid droplet catabolism: lipolysis, which utilizes the cAMP pathway to activate and recruit cytosolic lipases to the LD surface, and lipophagy, which utilizes membrane trafficking events that lead to LD breakdown by lysosomal lipases. Preliminary data suggest that lipolysis and lipophagy machinery target discrete, size-based LD subpopulations, and that small LDs are targeted for direct engulfment by multivesicular bodies (MVBs) for catabolism through the late endosomal pathway. Thus, the central hypothesis of this proposal is that EtOH disrupts a sequential mechanism whereby lipolysis acts on large LDs to reduce their size for direct uptake by endosomal microlipophagy. In Aim 1, I will determine the role of cytosolic lipases in protecting against ALD progression. In Aim 2, I will determine effect of EtOH on a sequential “lipolysis-to-lipophagy” pathway and define the mechanisms by which MVB/endosomes facilitate microlipophagy of small LDs. In Aim 3, I will integrate my previous expertise with this new knowledge and training to define novel cAMP signaling mechanisms that support lipolysis and lipophagy to combat alcoholic steatosis. The exceptionally strong research environment within Mayo Clinic’s Division of Gastroenterology and Hepatology is ideal for this training. To accomplish these aims, I will receive hands-on training in rodent models of chronic alcohol consumption, comparative proteomics, and bioinformatics. This new training complements my current skillset in cell signaling, microscopy, and biochemistry, and provides a multidisciplinary toolbox to comprehensively assess lipid catabolism in the liver. The proposed research will integrate my expertise in cAMP/PKA signaling mechanisms from my graduate school training with my postdoctoral expertise in lipid droplet biology and alcoholic steatosis. With the help of my mentor, Dr. Mark McNiven, along with a strong research team including two collaborators and four advisory committee members, I will have all the expertise and training needed to successfully accomplish these aims and transition to an independent research position. The results gained from the proposed research will provide a mechanistic understanding of lipid droplet catabolism in alcoholic fatty liver. Importantly, these studies will provide published research manuscripts and preliminary data in support of a future R01 proposal.

项目总结/文摘