Insulin action, reverse cholesterol transport, and HDL function

胰岛素作用、逆转胆固醇转运和 HDL 功能

基本信息

批准号：
8801085
负责人：
Rebecca Anne Haeusler
金额：
$ 40万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-21 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8801085
关键词：
Affect Apolipoproteins Arteries Atherosclerosis Cardiovascular Diseases Cardiovascular system Catabolism Cause of Death Cholesterol Cholesterol Esters Clinical Trials Data Defect Diabetes Mellitus Disease Dyes Enzymes Evans blue stain Excretory function Expenditure Feces Functional disorder Gene Expression Genes Glucose Health Healthcare Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Human Impairment Individual Insulin Insulin Resistance Intervention Investigation Knock-out Knockout Mice Light Link Lipids Lipoproteins Liver Measures Mediating Mediator of activation protein Metabolic syndrome Metabolism Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Phenotype Physiology Population Process Proteins Radiolabeled Regulation Risk Factors Role SR-BI receptor Serum Testing Therapeutic Intervention Tracer Transgenic Mice Triglycerides United States Work atheroprotective cardiovascular disorder risk endothelial dysfunction feeding hepatic lipase human NOS3 protein improved insight insulin signaling macrophage mouse model novel particle public health relevance radiotracer reverse cholesterol transport sphingosine 1-phosphate tool transcription factor uptake western diet

项目摘要

DESCRIPTION (provided by applicant): Dysregulation of high-density lipoprotein (HDL) turnover or function may contribute to the excess atherosclerosis in individuals with insulin-resistant (type 2) diabetes and metabolic syndrome. These conditions are characterized by low HDL. However, it is unknown how insulin regulates HDL in normal physiology, or in the pathophysiology of diabetes. FoxO1 is an insulin-repressible transcription factor that has emerged as a key mediator of insulin signaling in liver and the vessel wall. We have determined that FoxO1 regulates multiple genes critical for HDL metabolism and function, and mice lacking hepatic FoxO1 have alterations in HDL lipid and protein content. Thus, we propose that FoxO1 links insulin signaling and HDL. In Aim 1, we will investigate the hypothesis that FoxO1 regulates selective uptake of HDL-cholesterol in liver. We present preliminary data that FoxO1 regulates multiple steps in this process. In Aim 2, we will investigate the hypothesis that hepatic FoxO1 regulates macrophage-to-feces reverse cholesterol transport. We will determine the roles of individual HDL genes in the FoxO1 phenotype, and determine the effects on atherosclerosis. In Aim 3, we will investigate the hypothesis that FoxO1 regulates vasoprotective functions of HDL. We will examine the roles of FoxO1-regulated HDL components in endothelial barrier function and endothelial nitric oxide synthase activity. This work will build on novel hypotheses and a key mouse model to bring insight into the dysregulation of HDL during insulin resistance. The proposed studies will shed light on a key unanswered question in the pathophysiology of atherosclerosis, and reveal new targets for therapeutic intervention.

描述（由申请人提供）：高密度脂蛋白（HDL）营业额或功能的失调可能导致耐胰岛素耐药性（2型）糖尿病和代谢综合征的患者的过量动脉粥样硬化。这些条件的特征是低HDL。然而，尚不清楚胰岛素如何调节正常生理学或糖尿病的病理生理学中HDL。 FOXO1是一种胰岛素抑制的转录因子，已成为肝脏和血管壁中胰岛素信号传导的关键介体。我们已经确定FOXO1调节对HDL代谢和功能至关重要的多个基因，而缺乏肝FOXO1的小鼠在HDL脂质和蛋白质含量方面有改变。因此，我们提出FOXO1连接胰岛素信号传导和HDL。在AIM 1中，我们将研究FOXO1调节肝脏中HDL-胆固醇的选择性摄取的假设。我们提供了FOXO1在此过程中调节多个步骤的初步数据。在AIM 2中，我们将研究肝的假设 FOXO1调节巨噬细胞到fece的反向胆固醇运输。我们将确定单个HDL基因在FOXO1表型中的作用，并确定对动脉粥样硬化的影响。在AIM 3中，我们将研究FOXO1调节HDL血管保护功能的假设。我们将研究FOXO1调节的HDL成分在内皮屏障功能和内皮一氧化氮合酶活性中的作用。这项工作将基于新颖的假设和关键的小鼠模型，以使胰岛素抵抗期间HDL失调的洞察力。拟议的研究将阐明动脉粥样硬化病理生理学中的一个关键未解决问题，并揭示了治疗干预的新靶标。