Foxo1 in Triglyceride Metabolism

高甘油三酯血症是与胰岛素抵抗和2型有关的最常见的血脂紊乱。 糖尿病。它的特点是产量增加，富含甘油三酯(TG)的清除减少 极低密度脂蛋白(VLDL)。高甘油三酯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。我们的长期合作 目的是了解为什么胰岛素抵抗会导致VLDL-TG代谢异常，并导致 胰岛素抵抗肥胖者和2型糖尿病患者高甘油三酯血症的发生。狐狸醇 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。我们有 研究表明，Foxol调节肝脏载脂蛋白C-III(apoC-III)和微粒体的表达 甘油三酯转移蛋白(MTP)，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作用于 调节极低密度脂蛋白-甘油三酯的水解和清除，而MTP作用于控制极低密度脂蛋白的组装和清除 分泌物。这两个基因都受到胰岛素的生理抑制，并在反应中异常升高。 对胰岛素抵抗的影响。我们试图检验一种假设，即载脂蛋白C-III和MTP的异常表达 由于Foxol活性过高，导致胰岛素抵抗。我们提出了三个具体目标：1) 确定Foxol是否介导胰岛素对正常和糖尿病小鼠极低密度脂蛋白-甘油三酯代谢的作用； 2)确定Foxol是否在胰岛素抵抗与apoC-III过量产生之间起作用 高甘油三酯血症的发病机制；3)阐明Foxol通过MTP信号在高甘油三酯血症中的作用。 高甘油三酯血症肝脏VLDL-TG过度生成的发病机制。为了解决这些具体目标， 我们将使用基因转移和转基因方法来实现Foxol在体内的功能得失。 培养的肝细胞以及胰岛素作用受损和/或甘油三酯改变的小鼠的肝脏 新陈代谢。这些研究将有助于确定MTPand的胰岛素依赖调节机制 ApoC-III的产生，并阐明胰岛素抵抗与 高甘油三酯血症。

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.