Foxo1 in Triglyceride Metabolism

高胆固醇血症是最常见的与胰岛素抵抗和2型糖尿病相关的血脂紊乱。 糖尿病其特征在于富含甘油三酯（TG）的生成增加和清除减少。 极低密度脂蛋白（VLDL）。高胆固醇血症是糖尿病发病的主要危险因素， 动脉粥样硬化和冠状动脉疾病，但其病理生理学知之甚少。我们的长期 目的是了解为什么胰岛素抵抗导致VLDL-TG代谢异常，并导致 肥胖和2型糖尿病的胰岛素抵抗受试者中高胰岛素血症的发展。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。我们有 显示Foxol调节载脂蛋白C-III（apoC-III）和微粒体的肝表达， 甘油三酯转移蛋白（MTP），VLDL-TG代谢中的两个限速步骤。ApoC-III作用于 调节VLDL-TG水解和清除，而MTP功能是控制VLDL组装， 分泌物这两种基因在生理上都受到胰岛素的抑制，并且在反应中异常升高。 胰岛素抵抗我们试图验证apoC-III和MTP 1的异常表达是一个假设， 由于过量的Foxol活性，导致胰岛素抵抗。我们提出三个具体目标：1） 确定Foxol是否介导胰岛素对正常和糖尿病小鼠中VLDL-TG代谢的作用; 2)为了确定Foxol是否在胰岛素抵抗与apoC-III过度产生之间起作用， 3）阐明Foxol信号通过MTP在高脂血症发病机制中的作用， 高脂血症中肝脏VLDL-TG过度产生的发病机制为了实现这些具体目标， 我们将采用基因转移和转基因方法来实现Foxol功能的获得与丧失， 培养的肝细胞以及胰岛素作用受损和/或TG改变的小鼠的肝脏 新陈代谢.这些研究将有助于确定胰岛素依赖性调节MTP的机制， apoC-III的产生，并阐明胰岛素抵抗和 高胆固醇血症

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 MTPis 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 MTPand apoC-III production, and elucidate the molecular links between insulin resistance and hypertriglyceridemia.