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：
10455130
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/10455130
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.

项目概要/摘要我的长期目标是发现导致酒精肝的新细胞机制疾病（ALD），一种进行性疾病，导致不可逆转的阶段，可能致命。 ALD 的早期可逆前兆是酒精性脂肪变性，其中大量甘油三酯和富含胆固醇的脂滴 (LD) 在肝细胞内积聚，肝细胞是主要的功能细胞类型虽然 LD 被认为是 ALD 进展的核心，但细胞酒精破坏这些细胞器分解的机制很差为了解决这一重要的知识差距，该提案将定义协同作用。脂滴分解代谢的两个看似不同的过程之间：脂肪分解，利用 cAMP 途径激活胞质脂肪酶并将其募集到 LD 表面，并进行脂噬作用，利用膜运输事件导致 LD 被溶酶体脂肪酶分解。初步数据表明，脂肪分解和脂肪吞噬机制以离散的、基于大小的 LD 为目标亚群，并且小 LD 是被多泡体直接吞噬的目标（MVB）通过晚期内体途径进行分解代谢因此，这是这个的中心假设。提议认为，EtOH 破坏了脂解作用于大 LD 的顺序机制，从而减小它们的大小以便通过内体微脂自噬直接摄取。在目标 1 中，我将确定在目标 2 中，我将确定胞质脂肪酶在防止 ALD 进展中的作用。 EtOH 对连续的“脂肪分解到脂肪吞噬”途径的影响，并定义了其机制 MVB/内体促进小 LD 的微脂自噬在目标 3 中，我将整合我之前的研究。利用这些新知识和培训的专业知识来定义新颖的 cAMP 信号机制支持脂肪分解和脂肪吞噬以对抗酒精性脂肪变性。梅奥诊所胃肠病学和肝病科的环境非常适合此目的为了实现这些目标，我将接受慢性啮齿动物模型的实践培训。酒精消耗、比较蛋白质组学和生物信息学。补充了我目前在细胞信号传导、显微镜和生物化学方面的技能，并提供了综合评估肝脏脂质分解代谢的多学科工具箱。研究将整合我研究生在 cAMP/PKA 信号机制方面的专业知识我在学校接受了脂滴生物学和酒精性脂肪变性方面的博士后专业知识培训。在我的导师 Mark McNiven 博士和强大的研究团队（包括两名合作者和四名咨询委员会成员，我将拥有所有的专业知识和培训成功实现这些目标并过渡到独立研究所需的从拟议的研究中获得的结果将提供一个机制。重要的是，这些研究将了解酒精性脂肪肝中的脂滴分解代谢。提供已发表的研究手稿和初步数据以支持未来的 R01 提议。