Mechanisms of Lipid Heterogeneity in Lipid Droplet Catabolism

脂滴分解代谢中脂质异质性的机制

基本信息

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
项目类别：
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

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

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项目摘要

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：“脂质异质性在脂质液滴分解代谢中的机制” 脂质液滴（LD）分解代谢是一个基本过程，可以为迁移，诸如迁移，通过低营养利用率的时期分化和生存。异常LD分解代谢已被认可包括脂肪肝，肥胖，糖尿病，肾脏疾病和癌症在内的几种疾病。因为LD 分解代谢在细胞行为中起着基本作用，此过程的详细机械知识具有潜在揭示潜在治疗的新目标。该项目将确定细胞的机制访问存储的LD燃料。 LD通过在每个细胞中存储细胞内脂肪在细胞代谢中起关键作用跨多种物种类型。 LD被独特的磷脂单层包围，含有丰富的中性三酰甘油（TAG）和胆固醇酯（CE）形式的脂质，可以通过线粒体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/cAMP刺激募集了细胞质脂肪酶脂肪甘油三酸酯脂肪酶（ATGL）到LD表面，2）脂肪噬菌，这是分解代谢的末端阶段，其中LD被贩运通过自噬和/或内体蔬菜通过溶酶体降解。我们实验室支持的初步数据我们的中心假设是LD单层中的脂质物种是通过脂解和脂肪寄生的调节的 LD分解代谢期间的酶。在AIM 1中，我们将确定脂解酶ATGL在生产中的作用 LD表面上的DAG募集DAG效应，例如蛋白激酶C。在AIM 2中，我们将确定在LD运输到溶酶体期间，调节磷脂酰肌醇的磷酸化。从中得出的结果拟议的研究将提供对脂质液滴贩运和分解代谢的机械理解 LD单层调节的结果。此外，这项研究将有助于未来的发展研究项目赠款申请。