Insulin action, reverse cholesterol transport, and HDL function

描述（由申请人提供）：高密度脂蛋白（HDL）转换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。这些疾病的特点是低HDL。然而，胰岛素如何调节HDL在正常生理或糖尿病病理生理中的作用尚不清楚。fox01是一种胰岛素抑制转录因子，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FoxO1调节对HDL代谢和功能至关重要的多个基因，肝脏缺乏FoxO1的小鼠HDL脂质和蛋白质含量发生改变。因此，我们提出fox01连接胰岛素信号和HDL。在目的1中，我们将研究FoxO1调节肝脏中高密度脂蛋白胆固醇选择性摄取的假设。我们提供的初步数据表明fox01调控了这一过程中的多个步骤。在目的2中，我们将研究肝细胞凋亡的假设

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.