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.

项目总结：“脂质滴卡他赛中脂质异质性的机制” 脂滴（LD）催化是一个基本的过程，燃料的能量密集型细胞任务，如迁移， 分化，并通过低养分可用性时期的生存。在以下患者中识别出异常LD catalysts 几种疾病病理，包括脂肪肝、肥胖症、糖尿病、肾病和癌症。因为LD 催化剂在细胞行为中起着基础性作用，对这一过程的详细机制知识 有可能揭示潜在治疗的新靶点。这个项目将确定细胞 获取存储的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起关键作用 在多个物种中进行分类LDs被独特的磷脂单层所包围，含有丰富的中性 三酰甘油（TAG）和胆固醇酯（CE）形式的脂质，其可通过以下方式用于能量产生： 线粒体β-氧化。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） 脂解，其中β-肾上腺素能/cAMP刺激募集细胞质脂肪酶脂肪甘油三酯脂肪酶 （ATGL）至LD表面，和2）脂肪吞噬，其中LD被运输至 通过自噬和/或内体囊泡的溶酶体降解。我们实验室的初步数据支持 我们的中心假设是，LD单层内的脂质种类受到脂解和脂肪吞噬作用的调节 酶在LD催化期间。在目的1中，我们将确定脂肪分解酶ATGL在产生 在LD表面上的DAG以募集DAG效应物如蛋白激酶C。在目标2中，我们将确定 磷脂酰肌醇磷酸化的调节过程中LD运输到溶酶体。结果从 拟议的研究将提供一个机制的理解脂滴运输和catalysts作为一个 LD单层调制的结果。此外，这项研究将有助于未来开发更大的 研究项目补助金申请。