Foxo1 in Apoliprotein C-III & Triglyceride Metabolism

描述（由申请人提供）：高胆固醇血症是与胰岛素抵抗和2型糖尿病相关的最常见的脂质紊乱。其特征在于富含甘油三酯（TG）的极低密度脂蛋白（VLDL）的产生增加和清除减少。高脂血症是动脉粥样硬化和冠状动脉疾病发病机制的主要危险因素，但其病理生理机制知之甚少。我们的长期目标是了解为什么胰岛素抵抗会导致VLDL-TG代谢异常，并导致肥胖和2型糖尿病胰岛素抵抗受试者发生高甘油三酯血症。Foxol是一种转录因子，在介导胰岛素对基因表达的作用中起关键作用。我们已经证明Foxol调节载脂蛋白C-III（apoC-III）和微粒体甘油三酯转移蛋白（MTP）的肝脏表达，这是VLDL-TG代谢中的两个限速步骤。ApoC-III起调节VLDL-TG水解和清除的作用，而MTP起控制VLDL组装和分泌的作用。这两种基因在生理上都受到胰岛素的抑制，并且在对胰岛素抵抗的反应中异常升高。我们试图检验这一假设，即apoC-III和MTP的异常表达是由于过量的Foxol活性，导致胰岛素抵抗。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中胰岛素对VLDL-TG代谢的作用; 2）确定Foxol是否在高脂血症发病机制中将胰岛素抵抗与apoC-III过度产生联系起来发挥作用; 3）阐明Foxol通过MTP信号传导在高脂血症肝脏VLDL-TG过度产生发病机制中的作用。为了解决这些特定的目标，我们将采用基因转移和转基因方法来实现Foxol在培养的肝细胞以及胰岛素作用受损和/或TG代谢改变的小鼠肝脏中的功能获得与功能丧失。这些研究将有助于确定MTP和apoC-III产生的胰岛素依赖性调节机制，并阐明胰岛素抵抗和高脂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.