Mechanisms linking insulin action with lipoprotein metabolism

胰岛素作用与脂蛋白代谢的联系机制

• 批准号: 10207738
• 负责人: Rebecca Anne Haeusler
• 金额: $ 53.92万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207738
• 关键词: ADD-1 protein; Affect; Area; Arterial Fatty Streak; Atherosclerosis; Cardiovascular Diseases; Cause of Death; Data; Defect; Diabetes Mellitus; Disease; Disease Outcome; Exclusion; Family; Fatty Acids; Female; Foam Cells; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Glucose; Gold; Grant; Hepatic; Hyperinsulinism; Hypertriglyceridemia; Impairment; Individual; Inflammation; Insulin; Insulin Resistance; Kinetics; Knock-out; Knockout Mice; Light; Link; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Mediating; Metabolic; Metabolic syndrome; Metabolism; Molecular; Mus; Nuclear; Pathway interactions; Patients; Phenotype; Phosphorylation; Physiological; Plasma; Proteins; Radiolabeled; Regulation; Role; Techniques; Testing; Therapeutic Intervention; Tissues; Tracer; Transcriptional Regulation; Triglycerides; United States; Work; atherogenesis; cardiovascular risk factor; genetic manipulation; glucose production; hepatic lipase; improved; in vivo; insulin mediators; insulin signaling; lipid metabolism; lipoprotein lipase; lipoprotein triglyceride; macrophage; male; monocyte; precursor cell; progenitor; programs; transcription factor; uptake

Dysregulation of lipoprotein metabolism may contribute to the excess atherosclerosis in individuals with the metabolic syndrome. This condition is characterized by multiple defects in lipoprotein metabolism, including increases in triglyceride-rich lipoproteins (TRLs). Insulin resistance and hyperinsulinemia underlie the metabolic syndrome, however it is incompletely understood how insulin regulates TRL metabolism. Moreover, TRLs are associated with increased cardiovascular risk, but the mechanisms by which TRLs affect atherosclerosis are not fully known. FoxOs are insulin-repressible transcription factors that have emerged as key mediators of insulin signaling in liver. We’ve determined that FoxOs regulate TRL metabolism, and in this grant, we will determine the mechanisms of this pathway. We will also investigate the effects of this pathway on atherosclerosis. Our study will rely on lipoprotein turnover in vivo using kinetic studies with radiolabeled tracers, and we will use genetic rescue approaches to test causative mechanisms. We will examine effects of the hepatic FoxO-TRL pathway on atherosclerosis and macrophage dysfunctions. These studies will shed light on key unanswered questions in the pathophysiology of metabolic syndrome-related cardiovascular risk, and may reveal better approaches for therapeutic intervention.

脂蛋白代谢失调可能导致代谢综合征患者动脉粥样硬化过度。这种疾病的特征是脂蛋白代谢的多种缺陷，包括富含甘油三酯的脂蛋白（TRL）的增加。胰岛素抵抗和高胰岛素血症是代谢综合征的基础，但胰岛素如何调节TRL代谢尚不完全清楚。此外，TRL与心血管风险增加有关，但TRL影响动脉粥样硬化的机制尚不完全清楚。FoxO是胰岛素可抑制的转录因子，已成为肝脏中胰岛素信号传导的关键介质。我们已经确定FoxOs调节TRL代谢，在本研究中，我们将确定这一途径的机制。我们还将研究该途径对动脉粥样硬化的影响。我们的研究将依赖于体内脂蛋白周转使用放射性标记示踪剂的动力学研究，我们将使用遗传拯救方法来测试致病机制。我们将研究肝脏FoxO-TRL通路对动脉粥样硬化和巨噬细胞功能障碍的影响。这些研究将揭示代谢综合征相关心血管风险的病理生理学中关键的未回答的问题，并可能揭示更好的治疗干预方法。