Insulin action, reverse cholesterol transport, and HDL function

胰岛素作用、逆转胆固醇转运和 HDL 功能

• 批准号: 9270826
• 负责人: Rebecca Anne Haeusler
• 金额: $ 0.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/9270826
• 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; NOS3 gene; 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; improved; insight; insulin signaling; macrophage; mouse model; novel; particle; radiotracer; reverse cholesterol transport; sphingosine 1-phosphate; tool; transcription factor; uptake; western diet

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）周转或功能失调可能导致患有胰岛素抵抗（2 型）糖尿病和代谢综合征的个体出现过度动脉粥样硬化。这些病症的特点是高密度脂蛋白水平较低。然而，尚不清楚胰岛素如何在正常生理学或糖尿病病理生理学中调节高密度脂蛋白。 FoxO1 是一种胰岛素抑制转录因子，已成为肝脏和血管壁中胰岛素信号传导的关键介质。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，缺乏肝脏 FoxO1 的小鼠的 HDL 脂质和蛋白质含量发生变化。因此，我们提出 FoxO1 将胰岛素信号传导和 HDL 连接起来。在目标 1 中，我们将研究 FoxO1 调节肝脏中 HDL 胆固醇选择性摄取的假设。我们提供了 FoxO1 调节此过程中多个步骤的初步数据。在目标 2 中，我们将研究肝脏的假设 FoxO1 调节巨噬细胞到粪便的逆转胆固醇转运。我们将确定单个 HDL 基因在 FoxO1 表型中的作用，并确定其对动脉粥样硬化的影响。在目标 3 中，我们将研究 FoxO1 调节 HDL 的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。这项工作将建立在新的假设和关键小鼠模型的基础上，以深入了解胰岛素抵抗期间 HDL 的失调。拟议的研究将揭示动脉粥样硬化病理生理学中一个尚未解答的关键问题，并揭示治疗干预的新目标。