Foxo1 in Apoliprotein C-III & Triglyceride Metabolism

描述(申请人提供)：高甘油三酯血症是与胰岛素抵抗和2型糖尿病相关的最常见的血脂紊乱。它的特点是产量增加，富含甘油三酯(TG)的极低密度脂蛋白(VLDL)的清除量减少。高甘油三酯血症是动脉粥样硬化和冠状动脉疾病发病的主要危险因素，但其病理生理机制尚不清楚。我们的长期目标是了解为什么胰岛素抵抗会导致肥胖症和2型糖尿病患者的极低密度脂蛋白-甘油三酯代谢异常并导致高甘油三酯血症。Foxol是一种转录因子，在介导胰岛素对基因表达的作用中起着关键作用。我们已经证明，Foxol调节肝脏载脂蛋白C-III(apoC-III)和微粒体甘油三酯转移蛋白(MTP)的表达，这是极低密度脂蛋白-甘油三酯代谢的两个限速步骤。载脂蛋白C-III调节极低密度脂蛋白-甘油三酯的降解和清除，而MTP则控制极低密度脂蛋白的组装和分泌。这两个基因都受到胰岛素的生理抑制，并在胰岛素抵抗时异常升高。我们试图验证这一假设，即apoC-III和MTP的异常表达是由于胰岛素抵抗导致的Foxol活性过高。我们提出了三个具体目标：1)确定Foxol是否介导正常和糖尿病小鼠的胰岛素对VLDL-TG代谢的作用；2)确定Foxol是否在高甘油三酯血症的发病机制中发挥作用，将胰岛素抵抗与apoC-III过度产生联系起来；3)阐明Foxol通过MTP信号转导在高甘油三酯血症肝脏VLDL-TG过度产生的发病机制中的作用。为了解决这些特定的目标，我们将使用基因转移和转基因方法，在培养的肝细胞以及胰岛素作用受损和/或甘油三酯代谢改变的小鼠的肝脏中实现Foxol的获得和功能丧失。这些研究将有助于明确胰岛素依赖调节MTP和apoC-III产生的机制，并阐明胰岛素抵抗和高甘油三酯血症之间的分子联系。

DESCRIPTION (provided by applicant): Hypertriglyceridemia is the commonest lipid disorder associated with insulin resistance and type 2 diabetes. It is characterized by increased production and decreased clearance of triglyceride (TG)-rich very low-density lipoproteins (VLDL). Hypertriglyceridemia is a major risk factor for the pathogenesis of atherosclerosis and coronary artery disease, but its pathophysiology is poorly understood. Our long-term goal is to understand why insulin resistance causes abnormal VLDL-TG metabolism and results in the development of hypertriglyceridemia in insulin resistant subjects with obesity and type 2 diabetes. Foxol is a transcription factor that plays a key role in mediating insulin action on gene expression. We have shown that Foxol regulates hepatic expression of apolipoprotein C-III (apoC-III) and microsomal triglyceride transfer protein (MTP), two rate-limiting steps in VLDL-TG metabolism. ApoC-III acts to regulate VLDL-TG hydrolysis and clearance, whereas MTP functions to control VLDL assembly and secretion. Both genes are physiologically suppressed by insulin, and are abnormally elevated in response to insulin resistance. We seek to test the hypothesis that the aberrant expression of apoC-III and MTP is due to excessive Foxol activity, resulting from insulin resistance. We propose three specific aims: 1) To determine whether Foxol mediates insulin action on VLDL-TG metabolism in normal and diabetic mice; 2) To determine whether Foxol plays a role in linking insulin resistance to apoC-III overproduction in the pathogenesis of hypertriglyceridemia; 3) To elucidate the role of Foxol signaling through MTP in the pathogenesis of hepatic VLDL-TG overproduction in hypertriglyceridemia. To address these specific aims, we will employ gene transfer and transgenic approaches to achieve gain- vs. loss-of-function of Foxol in cultured hepatocytes as well as in livers of mice with impaired insulin action and/or altered TG metabolism. These studies will help define the mechanism of insulin-dependent regulation of MTP and apoC-III production, and elucidate the molecular links between insulin resistance and hypertriglyceridemia.