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.

项目概要/摘要 脂质提供丰富的能量来源来促进基本的细胞过程，包括迁移、 分化和在营养物质供应不足时期的生存。储存与利用 脂质燃料的产生依赖于脂滴（LD）。这些独特的细胞器被外围的 磷脂单层封装含有中性脂质三酰甘油 (TAG) 的核心 和胆固醇酯（CE）。 LD 拥有独特的蛋白质组，包括接头、酶和结构 直接与 LD 单层相互作用并调节生物发生和运输的蛋白质 分解代谢。然而，有关 LD 之间关系的详细机械知识 缺乏单层和 LD 贩运机制。这些知识对于 脂噬过程，LD 亚群选择性地靶向溶酶体 降解。我们的初步数据表明，LDs 在 LD单层水平，这种异质性影响某些小LD的命运 亚群走向脂肪吞噬。此外，我们假设 LD 单层的脂质 包括二酰甘油 (DAG) 和磷脂酰肌醇 (PI) 受 LD 分解代谢调节 酶来影响其贩运。在项目1中，我们将确定脂肪的作用 甘油三酯脂肪酶 (ATGL) 通过 TAG 水解在 LD 表面生成 DAG，并探索 DAG 对 LD 表面蛋白激酶 C (PKC) 募集和激活的影响。 在项目 2 中，我们将研究 Rab5 将 PI 3-激酶招募到 LD 表面进行磷酸化的过程 PI，定义了 ESCRT 蛋白在哺乳动物细胞自噬 LD 运输中的作用。 我们还将探索某些 ESRT 在 LD 生物发生中的意想不到的作用。取得的成果 拟议的研究将提供对脂滴运输的机制理解 以及LD单层的调制。