Insulin regulated hepatic apo B lipoprotein biogenesis

超出所提供的空间。 胰岛素对肝脏载脂蛋白B分泌的控制可能在平衡肠道与肝脏富脂蛋白（TRL）代谢中起调节作用。在包括糖尿病和肥胖症在内的胰岛素抵抗状态下，高胰岛素血症是加速动脉粥样硬化形成的一个因素，导致心脏病发作、中风和外周血管疾病。胰岛素通过减少合成和增加细胞内降解抑制肝载脂蛋白B，该途径由胰岛素受体介导。胰岛素受体特异性抵抗介导的载脂蛋白B抑制可导致TRL分泌增加，并加重餐后高脂血症。拟议的研究将该途径置于病理生理学背景中。激活的磷脂酰肌醇3-激酶（PI 3-K）靶向内质网（ER）并产生带电产物磷脂（PIP-3），可干扰载脂蛋白B的合成和分泌，导致载脂蛋白B降解。目的1是确定胰岛素抑制大鼠（B48/B100模型）、仓鼠（B100模型）和遗传改变小鼠（B100模型）中肝脏载脂蛋白B分泌的生理相关性，并确定短期高胰岛素血症导致肝脏载脂蛋白B的长期抑制，最大限度地减少肝脏和肠道脂蛋白颗粒之间的竞争。胰岛素对apo B抑制作用的丧失伴随胰岛素抵抗，导致不适当的apo B合成和分泌以及延长的餐后高脂血症Apo B代谢，将对胰岛素抵抗动物模型（包括Zucker糖尿病肥胖大鼠和果糖喂养仓鼠）进行表征。目的2：研究胰岛素抵抗模型中PI 3 K在内质网中的定位，探讨PI 3 K在内质网中的定位缺陷可能参与胰岛素抵抗的发生，并探讨胰岛素抵抗模型中PI 3 K在内质网中的定位缺陷对肝脏apo B分泌抑制的机制。胰岛素依赖的PI 3-K通路可能参与肝脏apo B的生物合成，这些研究将为胰岛素介导的胰岛素抵抗综合征高脂血症的特异性通路提供新的认识。性能现场=

EXCEED THE SPACE PROVIDED. Control of hepatic apo B secretion by insulin may serve a regulatory role in balancing intestinal vs. hepatic triglyceride-rich lipoprotein (TRL) metabolism. In insulin resistant states including diabetes and obesity hypertriglyceridemia is a factor in accelerated atherogenesis resulting in heart attacks, strokes, and peripheral vascular disease. Insulin suppresses hepatic apo B through decreased synthesis and increased intracellular degradation, and the pathway is mediated by the insulin receptor. Specific resistance of insulin receptor mediated inhibition of apo B, which may occur in obesity and diabetes, would result in increased numbers of secreted TRL and aggravate post-prandial hypertriglyceridemia. Proposed studies place the pathway into pathophysiologic context. Targeting of activated phosphoinositide 3-kinase (PI 3-K) to the endoplasmic reticulum (ER) and generation of charged product phospholipids (PIP-3) are proposed to interfere with apo B synthesis and secretion and result in apo B degradation. Aim 1 is to define the physiologic relevance of insulin to inhibit the secretion of hepatic apo B in rats (B48/B100 model), in hamsters (B100 model), and in genetically altered mice (B100 model) and establish that short term hyperinsulinemia results in longer term suppression of hepatic apo B, minimizing competition between hepatic and intestinal lipoprotein particles. Loss of the suppressive effect of insulin on apo B occurs with insulin resistance which results in inappropriate apo B synthesis and secretion and prolonged post-prandial hypertriglyceridemia Apo B metabolism in insulin resistant animal models including the Zucker Diabetic Fatty rat and fructose fed hamster will be characterized. Aim 2 is to determine signaling events mediated by PI 3-K resultant from translocation of activated PI 3-K into the ER and to determine the mechanism of resistance in this pathway in suppression of hepatic apo B secretion in insulin resistant models.The hypothesis is that defective localization of PI 3-K activity to specific ER compartments may be involved in insulin resistance. Specific insulin dependent PI 3-K pathways may be involved in hepatic apo B biogenesis and the proposed studies will provide new insight into specialized pathways mediated by insulin which are involved in the hypertriglyceridemia of insulin resistance syndromes. PERFORMANCE SITE ========================================Section End===========================================