Role of lipid droplets in insulin resistance

脂滴在胰岛素抵抗中的作用

基本信息

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
项目类别：
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

项目摘要

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.

该提案的中心假设是检验内皮 LD 周转对于正常生理过程中的代谢功能至关重要的观点。这一假设的一个推论是，血管中 LD 周转的损害将增强饮食诱导的胰岛素抵抗模型中的胰岛素抵抗状态。为了检验这一假设，提出了以下目标。 1：阐明ATGL在正常生理条件下和饮食诱导的胰岛素抵抗（IR）后调节EC中LD水解和炎症的作用； 2. 探究EC ATGL调节血管功能和细胞代谢的机制； 3：破译内皮 DGAT 对 LD 合成和炎症的重要性。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，从而有可能揭示内皮功能障碍和胰岛素抵抗之间的新联系。此外，目前毛细血管 EC 中 LPL 的 TG 脂解作用模型主要集中在代谢活跃的组织，如心脏和骨骼肌，这无法解释大血管 EC 中 LD 的形成，因此，我们的实验将超越教条，或许可以深入了解TG水平升高的2型糖尿病患者冠心病的发病率更高。