Role of lipid droplets in insulin resistance

脂滴在胰岛素抵抗中的作用

• 批准号: 10030642
• 负责人: William C Sessa
• 金额: $ 45.09万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10030642
• 关键词: Address; Adipocytes; Awareness; Biological Availability; Blood Vessels; Capillary Endothelial Cell; Cardiovascular system; Caveolae; Caveolins; Cell membrane; Cell physiology; Cells; Cellular biology; Complex; Coronary heart disease; Data; Diabetes Mellitus; Diet; Diglycerides; Disease; Dyslipidemias; Endothelial Cells; Endothelium; Energy-Generating Resources; Enzymes; Etiology; Event; Fatty acid glycerol esters; Genetic; Glycosylated hemoglobin A; Heart; Homeostasis; Hydrolysis; Hyperlipidemia; Hypertension; Hypertriglyceridemia; Impairment; In Vitro; Incidence; Inflammation; Insulin; Insulin Resistance; Kidney; Knowledge; LDL Cholesterol Lipoproteins; Laboratories; Link; Lipase; Lipids; Lipolysis; Liver; Metabolic; Metabolic syndrome; Metabolism; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Muscle Fibers; Myocardium; NOS3 gene; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Organelles; Outcome; Participant; Pathway interactions; Patients; Pharmacology; Physiological; Physiology; Prediabetes syndrome; Proteins; Public Health; Regulation; Research; Risk Factors; Role; Skeletal Muscle; Symptoms; Testing; Time; Tissues; Transferase; Triglyceride Metabolism; Triglycerides; Type 2 diabetic; Vascular Endothelium; Work; cardiovascular disorder risk; caveolin 1; diabetic patient; diacylglycerol O-acyltransferase; endoplasmic reticulum stress; endothelial dysfunction; experimental study; fatty acid oxidation; glycemic control; human subject; in vivo; insight; lipid metabolism; modifiable risk; mortality; novel; oxidation; sedentary lifestyle; synthetic enzyme; therapeutic target; uptake; western diet

The central hypothesis of this proposal is to test the idea that endothelial LD turnover is critical for metabolic function during normal physiology. A corollary to this hypothesis is that impairments in LD turnover in blood vessels will augment insulin resistant states in models of diet induced insulin resistance. To test this hypothesis, the following Aims are proposed. 1: To elucidate the role of ATGL in regulating LD hydrolysis in EC and inflammation under normal physiological conditions and after diet induced insulin resistance (IR); 2. To interrogate the mechanisms of how EC ATGL regulates vascular function and cellular metabolism; and 3: To decipher the importance of endothelial DGATs on LD synthesis and inflammation. Collectively, we will define for the first time the role of endothelial LD metabolism as it relates to the control of circulating TG and metabolic function, thus potentially uncovering a novel link between endothelial dysfunction and insulin resistance. Moreover, the current model of TG lipolysis by LPL in capillary EC is focused on metabolically active tissues such as heart and skeletal muscle and this cannot explain LD formation in large vessel EC, thus, our experiments will move beyond the dogma and perhaps yield insights into the higher incidence of coronary disease in type 2 diabetic patients with elevated TG levels.

该建议的中心假设是测试内皮LD周转在正常生理过程中对代谢功能至关重要的想法。这一假说的推论是，在饮食诱导的胰岛素抵抗模型中，血管中LD周转的损伤将增加胰岛素抵抗状态。为了验证这一假设，提出了以下目标。一曰：目的：1.阐明ATGL在正常生理条件下和饮食诱导胰岛素抵抗（IR）后调节内皮细胞LD水解和炎症反应中的作用。探讨EC ATGL调节血管功能和细胞代谢的机制; 3.阐明内皮DGAT在LD合成和炎症中的重要性。总的来说，我们将首次定义内皮LD代谢的作用，因为它与循环TG和代谢功能的控制有关，从而可能揭示内皮功能障碍和胰岛素抵抗之间的新联系。此外，目前的模型TG脂解的LPL在毛细血管EC是集中在代谢活性组织，如心脏和骨骼肌，这不能解释LD的形成在大血管EC，因此，我们的实验将超越教条，并可能产生洞察冠心病的发病率较高的2型糖尿病患者与TG水平升高。