Insulin regulated hepatic apo B lipoprotein biogenesis

胰岛素调节肝脏载脂蛋白 B 脂蛋白生物发生

• 批准号: 6874294
• 负责人: JANET DEHOFF SPARKS
• 金额: $ 26.52万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874294
• 关键词: adenosine triphosphate; apolipoprotein B; blood lipoprotein biosynthesis; endoplasmic reticulum; enzyme activity; exotoxins; hemolysin; immunoprecipitation; insulin; insulin receptor; laboratory rat; liver cells; microsomes; monoclonal antibody; obesity; phosphatidylinositol 3 kinase; phosphorylation; pore forming protein; protein sequence; protein transport; stoichiometry; tissue /cell culture; vesicle /vacuole

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===========================================

超出提供的空间。胰岛素控制肝脏载脂蛋白B的分泌可能在平衡肠道和肝脏富含甘油三酯的脂蛋白(TRL)代谢方面起到调节作用。在胰岛素抵抗状态，包括糖尿病和肥胖，高甘油三酯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脏载脂蛋白B，这一途径是由胰岛素受体介导的。胰岛素受体特异性抵抗介导的载脂蛋白B抑制可能发生在肥胖和糖尿病中，导致TRL分泌增加，加重餐后高甘油三酯血症。建议的研究将该途径置于病理生理学的背景下。激活的磷脂酰肌醇3-激酶(PI3-K)靶向内质网(ER)和产生带电产物磷脂(PIP-3)干扰载脂蛋白B的合成和分泌，导致载脂蛋白B的降解。目的1是确定胰岛素抑制大鼠(B48/B100模型)、仓鼠(B100模型)和转基因小鼠(B100模型)肝脏载脂蛋白B分泌的生理学相关性，并建立短期高胰岛素血症导致长期抑制肝脏载脂蛋白B的结果，从而减少肝脏和肠道脂蛋白颗粒之间的竞争。胰岛素抵抗时，胰岛素对载脂蛋白B的抑制作用丧失，导致载脂蛋白B的不适当合成和分泌，以及餐后高甘油三酯血症的持续代谢。本文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的仓鼠进行描述。目的2确定活化的PI 3-K转位到内质网所产生的PI 3-K介导的信号转导事件，并探讨在胰岛素抵抗模型中这一途径抑制肝脏载脂蛋白B分泌的机制。假设PI 3-K活性缺陷地定位于特定的ER区可能参与胰岛素抵抗。胰岛素依赖的PI3-K途径可能参与肝脏载脂蛋白B的生物发生，本研究将为胰岛素介导的参与胰岛素抵抗综合征高甘油三酯血症的特殊途径提供新的认识。表演网站========================================Section End===========================================

项目成果

Suppression of the protein tyrosine phosphatase LAR reduces apolipoprotein B secretion by McA-RH7777 rat hepatoma cells.

抑制蛋白酪氨酸磷酸酶 LAR 可减少 McA-RH7777 大鼠肝癌细胞的载脂蛋白 B 分泌。

• DOI: 10.1006/bbrc.1997.7142
• 发表时间: 1997
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Phung,TL;Mooney,RA;Kulas,DT;Sparks,CE;Sparks,JD
• 通讯作者: Sparks,JD

Ethanol increases apolipoprotein B mRNA editing in rat primary hepatocytes and McArdle cells.

• DOI: 10.1006/bbrc.1998.9647
• 发表时间: 1998-11
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: D. Van Mater;M. Sowden;J. Cianci;J. Sparks;C. Sparks;N. Ballatori;H. C. Smith

Folate status modulates the induction of hepatic glycine N-methyltransferase and homocysteine metabolism in diabetic rats.

叶酸状态调节糖尿病大鼠肝甘氨酸 N-甲基转移酶和同型半胱氨酸代谢的诱导。

• DOI: 10.1152/ajpendo.00237.2006
• 发表时间: 2006
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Nieman,KristinM;Hartz,CaraS;Szegedi,SandraS;Garrow,TimothyA;Sparks,JanetD;Schalinske,KevinL
• 通讯作者: Schalinske,KevinL

Lipoprotein alterations in 10- and 20-week-old Zucker diabetic fatty rats: hyperinsulinemic versus insulinopenic hyperglycemia.

10 周和 20 周龄 Zucker 糖尿病脂肪大鼠的脂蛋白变化：高胰岛素血症与胰岛素缺乏性高血糖。

• DOI: 10.1016/s0026-0495(98)90298-0
• 发表时间: 1998
• 期刊: Metabolism: clinical and experimental
• 作者: Sparks,JD;Phung,TL;Bolognino,M;Cianci,J;Khurana,R;Peterson,RG;Sowden,MP;Corsetti,JP;Sparks,CE
• 通讯作者: Sparks,CE