Mechanisms linking insulin action with lipoprotein metabolism

脂蛋白代谢紊乱可能是代谢综合征患者过度动脉粥样硬化的原因之一。这种情况的特点是脂蛋白代谢的多种缺陷，包括富含甘油三酯的脂蛋白(TRL)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是胰岛素抑制转录因子，在肝脏中作为胰岛素信号的关键介质出现。我们已经确定FOXO调节TRL代谢，在这项资助中，我们将确定这一途径的机制。我们还将研究这一途径在动脉粥样硬化中的作用。我们的研究将依赖于体内脂蛋白的转化，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通路在动脉粥样硬化和巨噬细胞功能障碍中的作用。这些研究将阐明代谢综合征相关心血管风险的病理生理学中尚未回答的关键问题，并可能揭示更好的治疗干预方法。

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.