Mechanisms of Lipid Heterogeneity in Lipid Droplet Catabolism

脂滴分解代谢中脂质异质性的机制

• 批准号: 10714244
• 负责人: Micah Schott
• 金额: $ 28.09万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-16 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714244
• 关键词: Address; Adipose tissue; Adrenergic Agents; Alcoholic Liver Diseases; Applications Grants; Binding; Biochemical; Biological Assay; Cartoons; Catabolic Process; Catabolism; Cell Line; Cells; Cellular Metabolic Process; Centers of Research Excellence; Cholesterol Esters; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Core Facility; Custom; Cyclic AMP; Cytoplasm; Data; Development; Diabetes Mellitus; Diglycerides; Disease; Docking; Early Endosome; Endocytic Vesicle; Endosomes; Enzymes; Fatty Liver; Fatty acid glycerol esters; Funding; Future; Guanosine Triphosphate Phosphohydrolases; Heterogeneity; Hydrolysis; Hydrophobicity; Kidney Diseases; Knock-out; Knowledge; Laboratories; Lipase; Lipids; Lipolysis; Liver; Lysosomes; Mitochondria; Molecular Target; Monomeric GTP-Binding Proteins; Nebraska; Nutrient availability; Obesity; PIK3CG gene; Pathologic; Pathology; Pathway interactions; Phosphatidylinositols; Phospholipids; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Process; Production; Protein Family; Protein Kinase C; Proteins; Rattus; Regulation; Renal carcinoma; Research; Research Project Grants; Role; Signal Pathway; Surface; Tacrolimus Binding Proteins; Testing; Triglycerides; Vesicle; Work; aqueous; cell behavior; cell type; insight; lipidomics; migration; monolayer; novel; oxidation; recruit; synergism; trafficking

Project Summary: "Mechanisms of Lipid Heterogeneity in Lipid Droplet Catabolism" Lipid droplet (LD) catabolism is a fundamental process that fuels energy-intensive cellular tasks like migration, differentiation, and survival through periods of low nutrient availability. Aberrant LD catabolism is recognized in several disease pathologies including fatty liver, obesity, diabetes, kidney disease and cancer. Because LD catabolism plays a foundational role in cell behavior, detailed mechanistic knowledge of this process has the potential to reveal novel targets for potential therapy. This project will determine mechanisms by which cells access the stored LD fuel. LDs play critical roles in cell metabolism by storing intracellular fat in nearly every cell type across multiple species. Surrounded by a unique phospholipid monolayer, LDs contain abundant neutral lipids in the form of triacylglycerol (TAG) and cholesterol ester (CE) that can be utilized for energy production via mitochondrial β-oxidation. Release of these stored lipids requires synergy between two catabolic processes: 1) lipolysis, in which β-adrenergic/cAMP stimulation recruits the cytoplasmic lipase adipose triglyceride lipase (ATGL) to the LD surface, and 2) lipophagy, a terminal stage of catabolism in which LDs are trafficked for lysosomal degradation via autophagic and/or endosomal vesicles. Preliminary data from our laboratory supports our central hypothesis that lipid species within the LD monolayer are modulated by lipolysis and lipophagy enzymes during LD catabolism. In Aim 1, we will determine the role of the lipolysis enzyme ATGL in producing DAG on the LD surface to recruit DAG effectors such as protein kinase C. In Aim 2, we will determine the regulation of phosphatidylinositol phosphorylation during LD trafficking to lysosomes. The results gained from the proposed research will provide a mechanistic understanding of lipid droplet trafficking and catabolism as a result of modulation of the LD monolayer. Moreover, this research will aid in future development of larger research project grant applications.

项目摘要：“脂滴分解代谢中脂质异质性的机制” 脂滴 (LD) 分解代谢是一个基本过程，可促进能量密集型细胞任务，例如迁移、 低营养可用性时期的分化和存活被认为是异常的 LD 分解代谢。 多种疾病病理包括脂肪肝、肥胖、糖尿病、肾病和癌症。 分解代谢在细胞行为中起着基础作用，该过程的详细机制知识具有 揭示潜在治疗新靶标的潜力 该项目将确定细胞的机制。 获取储存的 LD 燃料，LD 通过在几乎每个细胞中储存细胞内脂肪，在细胞代谢中发挥关键作用。 LD 被独特的磷脂单层包围，含有丰富的中性物质。 三酰甘油 (TAG) 和胆固醇酯 (CE) 形式的脂质可用于通过以下方式产生能量 这些储存的脂质的释放需要两个分解代谢过程之间的协同作用：1) 脂肪分解，其中 β-肾上腺素能/cAMP 刺激招募细胞质脂肪酶脂肪甘油三酯脂肪酶 (ATGL) 到 LD 表面，以及 2) 脂噬作用，这是分解代谢的一个终末阶段，其中 LD 被贩运用于 我们实验室的初步数据支持通过自噬和/或内体囊泡进行溶酶体降解。 我们的中心假设是 LD 单层内的脂质种类受到脂肪分解和脂肪吞噬的调节 在目标 1 中，我们将确定脂肪分解酶 ATGL 在产生过程中的作用。 LD 表面上的 DAG 来招募 DAG 效应子，例如蛋白激酶 C。在目标 2 中，我们将确定 LD 运输至溶酶体过程中磷脂酰肌醇磷酸化的调节。 拟议的研究将提供对脂滴运输和分解代谢作为一种机制的机制理解。 此外，这项研究将有助于未来开发更大的LD单层。 研究项目资助申请。