The role of PLTP in BLp metabolism and atherogenesis

描述(由申请人提供)：分泌物增加和更高水平的 含载脂蛋白B的脂蛋白(BLP)是引起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 蛋白质(PLTP)介导磷脂在BLP和BLP之间的转移 高密度脂蛋白在血管内代谢中的作用，以解决PLTP的可能作用 在血脂异常和动脉粥样硬化中，培育PLTP基因敲除(PLTPO)小鼠 不同的高脂血症菌株。在apoB转基因(ApoBTg)和apoE中 基因敲除(ApoE0)背景，PLTP缺乏导致产量下降 和BLP水平，并明显减轻动脉粥样硬化。BLP分泌物 PLTP缺陷小鼠肝细胞减少，这一效应被取消 当PLTP被重新引入腺病毒中时。初步研究显示， PLTP在调节BLP的分泌方面发挥了重要且相当出人意料的作用。 BLP的生物合成是一个两步过程：apoB的初始脂肪合成 发生在内质网中，需要 微粒体甘油三酯转移蛋白。很难理解的，更慢的一秒 这一步可能包括在新生的非常 低密度脂蛋白(VLDL)颗粒。我们的工作假设是PLTP 可能参与了新生BLP的第二个脂肪修复步骤。初步 研究还表明，载脂蛋白B的产生不受低密度脂蛋白受体基因的影响 基因敲除(LDLrO)/PLTPO小鼠与LDLrO小鼠比较，但这会导致动脉粥样硬化 损伤显著减少，这表明：1)PLTP对 BLP的产生可能需要功能性的低密度脂蛋白受体的存在，在 在肝脏中最少；2)除了降低，还有一些未知的因素 BLP，参与了PLTPO小鼠动脉粥样硬化的减轻。的目标是 本项目旨在进一步研究PLTP在BLP代谢和代谢中的作用。 动脉硬化。具体目标是：1)评估PLTP可能 在非脂蛋白产生模型中参与BLP的组装和分泌 系统(PLTP、apoB和MTP共转染)、原代肝细胞和肝癌 细胞(类肝细胞)；2)评估PLTP发挥作用的假说 BLP在肠道细胞中的组装和分泌；3)确定 PLTPO小鼠除降低BLP外的抗动脉粥样硬化机制。这个项目 将提供关于PLTP活动和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 评价PLTP作为治疗靶点。

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.