Mechanisms of endosomal trafficking in lipid droplet catabolism

脂滴分解代谢中的内体运输机制

• 批准号: 10714356
• 负责人: Micah Schott
• 金额: $ 38.19万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714356
• 关键词: Address; Adipose tissue; Biogenesis; Catabolism; Cell physiology; Cholesterol Esters; Data; Diabetes Mellitus; Diglycerides; Disease; Encapsulated; Endosomes; Energy-Generating Resources; Enzymes; Fatty Liver; Health; Heterogeneity; Human; Hydrolysis; Kidney Diseases; Knowledge; Lipase; Lipids; Mammalian Cell; Mediating; Nutrient availability; Obesity; Organelles; Peripheral; Phospholipids; Phosphorylation; Phosphotransferases; Process; Protein Kinase C; Proteins; Proteome; Renal carcinoma; Research; Role; Structural Protein; Surface; Triglycerides; improved; lipid transport; migration; monolayer; protein activation; public health relevance; recruit; trafficking

Project Summary/Abstract Lipids provide a rich source of energy to fuel fundamental cellular processes including migration, differentiation, and survival through periods of low nutrient availability. The storage and utilization of lipid fuel relies on lipid droplets (LD). These unique organelles are surrounded by peripheral phospholipid monolayer that encapsulate a core containing neutral lipids triacylglycerol (TAG) and cholesterol ester (CE). LDs possess a unique proteome of adapters, enzymes, and structural proteins that interact directly with the LD monolayer and regulate trafficking for biogenesis and catabolism. However, detailed mechanistic knowledge regarding the relationship between the LD monolayer and LD trafficking machinery is lacking. This knowledge is especially critical for the process of lipophagy, whereby subpopulations of LDs are selectively targeted for lysosomal degradation. Our preliminary data suggest that LDs possess heterogenous lipid signatures at the level of the LD monolayer, and this heterogeneity influences the fate of certain small LD subpopulations toward lipophagy. Furthermore, we postulate that lipids of the LD monolayer including diacylglycerol (DAG) and phosphatidtyliositol (PI) are modulated by LD catabolic enzymes to influence their trafficking. In Project 1, we will determine the role of adipose triglyceride lipase (ATGL) in generating DAG on the LD surface via TAG hydrolysis, and explore the impact of DAG on the recruitment and activation of protein kinase C (PKC) on the LD surface. In Project 2, we will investigate Rab5 in recruiting PI 3-Kinases to the LD surface to phosphorylate PI, define the role of ESCRT proteins in the trafficking of LDs for lipophagy in mammalian cells. We will also explore an unexpected role for certain ESCRTs in LD biogenesis. The results gained from the proposed research will provide a mechanistic understanding of lipid droplet trafficking and the modulation of the LD monolayer.

项目摘要/摘要 脂质为燃料基本细胞过程提供了丰富的能源，包括迁移， 通过低营养利用率的时期分化和生存。存储和利用 脂质燃料依赖于脂质液滴（LD）。这些独特的细胞器被周围包围 磷脂单层封装了一个含有中性脂质三酰基甘油（TAG）的核心 和胆固醇酯（CE）。 LD具有独特的衔接，酶和结构的蛋白质组 与LD单层直接相互作用并调节贩运生物发生和 分解代谢。但是，有关LD之间关系的详细机械知识 缺乏单层和LD贩运机械。这些知识对于 寄生虫的过程，从而选择性地将LDS的亚群用于溶酶体 降解。我们的初步数据表明，LDS在 LD单层的水平，这种异质性影响了某些小LD的命运 朝向脂肪的亚群。此外，我们假设LD单层的脂质 包括二酰基甘油（DAG）和磷酸二苯乙醇醇（PI）由LD分解代谢调节 酶影响其贩运。在项目1中，我们将确定脂肪的作用 甘油三酸酯脂肪酶（ATGL）通过TAG水解在LD表面产生DAG，然后探索 DAG对蛋白激酶C（PKC）募集和激活对LD表面的影响。 在项目2中，我们将研究RAB5在募集PI 3-激酶至LD表面以磷酸化 PI，定义了ESCRT蛋白在LDS在哺乳动物细胞中的运输中的作用。 我们还将探索某些ESCRT在LD生物发生中的意外作用。结果获得了 从拟议的研究中，将提供对脂质液滴贩运的机械理解 以及LD单层的调制。