The role of PLTP in BLp metabolism and atherogenesis

PLTP 在 BLp 代谢和动脉粥样硬化形成中的作用

基本信息

批准号：
6622791
负责人：
XIAN-CHENG JIANG
金额：
$ 30.6万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2006-03-31
项目状态：
已结题

项目摘要

Description (Provided by applicant): Increased secretion and higher levels of apoB-containing lipoproteins (BLp) are a major cause of the dyslipidemia seen in familial hyperlipidemia, obesity, and diabetes. Plasma phospholipid transfer protein (PLTP) is known to mediate transfer of phospholipids between BLp and HDL during their intravascular metabolism, To address a possible role of PLTP in dyslipidemia and atherogenesis, PLTP gene knock-out (PLTPO) mice were bred with differing hyperlipidemic strains. In the apoB transgenic (apoBTg) and apoE knock-out (apoE0) backgrounds, PLTP deficiency resulted in reduced production and levels of BLp, and markedly decreased atherosclerosis. BLp secretion was diminished in hepatocytes from PLTP-deficient mice, an effect that was canceled when PLTP was reintroduced in the adenovirus. Preliminary studies reveal a major and quite unexpected role for PLTP in regulating the secretion of BLp. The biosynthesis of BLp is a two-step process: initial lipidation of apoB occurs in the endoplasmic reticulum, and requires the activity of the microsomal triglyceride transfer protein. A poorly understood, slower second step probably involves the addition of further lipid to the nascent very low-density lipoprotein (VLDL) particle. Our working hypothesis is that PLTP may be involved in the second lipidation step of nascent BLp. Preliminary studies also show that apoB production is not affected in LDL receptor gene knock-out (LDLrO)/PLTPO mice compared with LDLrO mice, but that atherosclerotic lesions are significantly reduced, suggesting that: 1) the influence of PLTP on the production of BLp may require the presence of functional LDL receptors, at least in the liver; and 2) there are some unknown factors, other than lowering BLp, involved in the reduction of atherosclerosis in PLTPO mice. The goal of this project is to investigate further the role of PLTP in BLp metabolism and atherosclerosis. Specific aims are: 1) to evaluate the hypothesis that PLTP may play a role in BLp assembly and secretion in nonlipoprotein-producing model systems (cotransfected by PLTP, apoB, and MTP), primary hepatocyte and hepatoma cells (liver-like cells); 2) to evaluate the hypothesis that PLTP plays a role in BLp assembly and secretion in intestinal cells; and 3) to determine antiatherogenic mechanisms in PLTPO mice other than lowering BLp. This project will provide new information on the relationship between PLTP activity and BLp production, between PLTP activity and atherosclerosis, and will further evaluate PLTP as a therapeutic target.

描述（由申请人提供）：分泌增加且水平更高含 apoB 的脂蛋白 (BLp) 是血脂异常的主要原因家族性高脂血症、肥胖症和糖尿病。血浆磷脂转移已知 PLTP 蛋白可介导 BLp 和 BLp 之间的磷脂转移。 HDL 在血管内代谢过程中，探讨 PLTP 的可能作用在血脂异常和动脉粥样硬化中，培育了 PLTP 基因敲除（PLTPO）小鼠与不同的高脂血症菌株。在 apoB 转基因 (apoBTg) 和 apoE 中敲除 (apoE0) 背景、PLTP 缺乏导致产量减少和 BLp 水平，并显着降低动脉粥样硬化。 BLp 分泌量为 PLTP 缺陷小鼠的肝细胞减少，这一效应被取消当PLTP被重新引入腺病毒中时。初步研究表明 PLTP 在调节 BLp 分泌中发挥着重要且相当出乎意料的作用。 BLp 的生物合成分为两步：apoB 的初始脂化发生在内质网中，并且需要微粒体甘油三酯转移蛋白。一个不太理解的、较慢的第二个步骤可能涉及向新生的非常多的物质添加更多的脂质低密度脂蛋白（VLDL）颗粒。我们的工作假设是 PLTP 可能参与新生 BLp 的第二个脂化步骤。初步的研究还表明 LDL 受体基因中 apoB 的产生不受影响敲除 (LDLrO)/PLTPO 小鼠与 LDLrO 小鼠相比，但动脉粥样硬化病变明显减少，提示：1）PLTP对 BLp 的产生可能需要功能性 LDL 受体的存在，肝脏最少； 2）除了降低之外，还有一些未知因素 BLp，参与减少 PLTPO 小鼠的动脉粥样硬化。目标是本项目旨在进一步研究PLTP在BLp代谢中的作用以及动脉粥样硬化。具体目标是：1）评估 PLTP 可能的假设在非脂蛋白产生模型中 BLp 组装和分泌中发挥作用系统（PLTP、apoB 和 MTP 共转染）、原代肝细胞和肝癌细胞（肝样细胞）； 2）评估PLTP发挥作用的假设参与肠细胞中 BLp 的组装和分泌； 3) 确定除了降低 BLp 之外，PLTPO 小鼠的抗动脉粥样硬化机制。这个项目将提供有关 PLTP 活性和 BLp 之间关系的新信息 PLTP 活性与动脉粥样硬化之间的关系，并将进一步评估 PLTP 作为治疗靶点。