权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10643896
负责人：
Carlos Fernandez Hernando
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/10643896
关键词：
Acceleration Adipocytes Awareness Biological Availability Blood Vessels Capillary Endothelial Cell Cardiovascular system Caveolae Caveolins Cell Line Cell membrane Cell physiology Cells Cellular biology Complex Coronary heart disease Cytoprotection 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 Physiological Physiology Prediabetes syndrome Proteins Public Health Regulation Research Risk Factors Role Skeletal Muscle Stroke 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 pharmacologic 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.

本提案的中心假设是测试内皮细胞LD转换在正常生理过程中对代谢功能至关重要的观点。这一假设的一个推论是，在饮食诱导的胰岛素抵抗模型中，血管中LD转换的损伤会增加胰岛素抵抗状态。为了验证这一假设，提出了以下目标。1：阐明ATGL在正常生理条件下和饮食诱导胰岛素抵抗（IR）后调节EC中LD水解和炎症的作用；2. 探讨EC ATGL调控血管功能和细胞代谢的机制；3：揭示内皮dgat在LD合成和炎症中的重要性。总的来说，我们将首次确定内皮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，目前毛细管EC中LPL对TG脂解的模型主要集中在代谢活跃的组织，如心脏和骨骼肌，这并不能解释大血管EC中LD的形成，因此，我们的实验将超越教条，可能会对TG水平升高的2型糖尿病患者冠状动脉疾病发病率更高的原因有所了解。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting the vasculature in cardiometabolic disease.

DOI：
10.1172/jci148556
发表时间：
2022-03-15
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Boutagy NE;Singh AK;Sessa WC
通讯作者：
Sessa WC

BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells.

DOI：
10.1074/jbc.ra120.015680
发表时间：
2020-12-25
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Tao B;Kraehling JR;Ghaffari S;Ramirez CM;Lee S;Fowler JW;Lee WL;Fernandez-Hernando C;Eichmann A;Sessa WC
通讯作者：
Sessa WC

An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells.

DOI：
10.1038/s41467-023-39514-1
发表时间：
2023-06-26
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Zhou, Wenping;Li, Wenxue;Wang, Shisheng;Salovska, Barbora;Hu, Zhenyi;Tao, Bo;Di, Yi;Punyamurtula, Ujwal;Turk, Benjamin E. E.;Sessa, William C. C.;Liu, Yansheng
通讯作者：
Liu, Yansheng

Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells.

DOI：
10.7554/elife.79529
发表时间：
2022-08-12
期刊：
ELIFE
影响因子：
7.7
作者：
Fowler, Joseph Wayne M.;Zhang, Rong;Tao, Bo;Boutagy, Nabil E.;Sessa, William C.
通讯作者：
Sessa, William C.

A Vectorial, ER-Mitochondria Link to Energy Homeostasis in the Vascular Endothelium.