Insulin action, reverse cholesterol transport, and HDL function

描述（由申请方提供）：高密度脂蛋白（HDL）周转或功能失调可能导致胰岛素抵抗（2型）糖尿病和代谢综合征患者的过度动脉粥样硬化。这些病症的特征是低HDL。然而，目前尚不清楚胰岛素如何在正常生理学或糖尿病的病理生理学中调节HDL。FoxO 1是一种胰岛素抑制性转录因子，已成为肝脏和血管壁胰岛素信号传导的关键介质。我们已经确定FoxO 1调节HDL代谢和功能的多个关键基因，缺乏肝脏FoxO 1的小鼠HDL脂质和蛋白质含量发生改变。因此，我们建议FoxO 1链接胰岛素信号和HDL。在目的1中，我们将研究FoxO 1调节肝脏中HDL-胆固醇的选择性摄取的假设。我们目前的初步数据表明，FoxO 1调节在这个过程中的多个步骤。在目标2中，我们将研究肝脏 FoxO 1调节巨噬细胞至粪便的胆固醇逆向转运。我们将确定单个HDL基因在FoxO 1表型中的作用，并确定其对动脉粥样硬化的影响。在目的3中，我们将研究FoxO 1调节HDL的血管保护功能的假设。我们将研究FoxO 1调节的HDL组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一个关键的小鼠模型，使深入了解胰岛素抵抗期间HDL的失调。这些研究将揭示动脉粥样硬化病理生理学中一个关键的未回答的问题，并揭示治疗干预的新靶点。

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.