Foxo1 in Triglyceride Metabolism

高甘油三酯血症是与胰岛素抵抗和 2 型相关的最常见的脂质疾病 糖尿病。其特点是富含甘油三酯 (TG) 的产量增加和清除率降低 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 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 患有肥胖和 2 型糖尿病的胰岛素抵抗受试者出现高甘油三酯血症。福克索 是一种转录因子，在介导胰岛素对基因表达的作用中发挥关键作用。我们有 表明 Foxol 调节载脂蛋白 C-III (apoC-III) 和微粒体的肝脏表达 甘油三酯转移蛋白 (MTP)，VLDL-TG 代谢中的两个限速步骤。 ApoC-III 的作用是 调节 VLDL-TG 水解和清除，而 MTP 则控制 VLDL 组装和清除 分泌。这两个基因在生理上都受到胰岛素的抑制，并且在响应中异常升高 到胰岛素抵抗。我们试图检验 apoC-III 和 MTP 的异常表达这一假设 由于Foxol活性过高，产生胰岛素抵抗。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 VLDL-TG 代谢的作用； 2) 确定 Foxol 是否在胰岛素抵抗与 apoC-III 过量产生之间发挥作用 高甘油三酯血症的发病机制； 3) 阐明Foxol信号通过MTP在 高甘油三酯血症中肝脏 VLDL-TG 过量产生的发病机制。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 改变的小鼠肝脏 新陈代谢。这些研究将有助于明确 MTP 的胰岛素依赖性调节机制 apoC-III 的产生，并阐明胰岛素抵抗和 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.