Insulin action, reverse cholesterol transport, and HDL function

描述(由申请人提供)：高密度脂蛋白(高密度脂蛋白)代谢或功能的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。这些情况的特点是高密度脂蛋白含量低。然而，在正常生理或糖尿病的病理生理学中，胰岛素是如何调节高密度脂蛋白的，目前还不清楚。Foxo1是一种胰岛素抑制转录因子，在肝脏和血管壁中是胰岛素信号的关键介质。我们已经确定FoxO1调节多个对高密度脂蛋白代谢和功能至关重要的基因，而缺乏肝脏FoxO1的小鼠的高密度脂蛋白和蛋白质含量发生了变化。因此，我们认为FoxO1将胰岛素信号与高密度脂蛋白联系起来。在目标1中，我们将研究FoxO1调节肝脏选择性摄取高密度脂蛋白-胆固醇的假说。我们提供了FoxO1在这一过程中调节多个步骤的初步数据。在目标2中，我们将调查肝脏的假设 Foxo1调节巨噬细胞到粪便的反向胆固醇运输。我们将确定单个高密度脂蛋白基因在FoxO1表型中的作用，并确定其在动脉粥样硬化中的作用。在目标3中，我们将研究FoxO1调节高密度脂蛋白的血管保护功能的假设。我们将研究FoxO1调节的高密度脂蛋白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上，以深入了解胰岛素抵抗期间高密度脂蛋白的失调。拟议的研究将阐明动脉粥样硬化病理生理学中一个关键的未解答的问题，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.