The role of PLTP in BLp metabolism and atherogenesis

描述（由申请人提供）：分泌增加， 含载脂蛋白B的脂蛋白（BLp）是导致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 已知蛋白质（PLTP）介导磷脂在BLp和BLp之间的转移， HDL在其血管内代谢过程中，为了解决PLTP的可能作用， 在血脂异常和动脉粥样硬化形成中，饲养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 敲除（apoE 0）背景下，PLTP缺陷导致生产减少 和BLp水平，并显著降低动脉粥样硬化。BLp分泌为 在PLTP缺陷小鼠的肝细胞中减少， 当PLTP被重新引入腺病毒时。初步研究显示， PLTP在调节BLp分泌中的主要和相当意想不到的作用。 BLp的生物合成是一个两步过程：apoB的初始脂化 发生在内质网中，并需要 微粒体甘油三酯转移蛋白。一个不太了解的，较慢的第二个 这一步可能涉及向新生的非常 低密度脂蛋白（VLDL）颗粒。我们的假设是PLTP 可能参与新生BLp的第二个脂化步骤。初步 研究还表明，载脂蛋白B的产生不受LDL受体基因的影响， 敲除（LDLrO）/PLTPO小鼠与LDLrO小鼠相比， 病变明显减少，表明：1）PLTP对 BLp的产生可能需要功能性LDL受体的存在， 最少在肝脏;和2）有一些未知的因素，除了降低 BLp参与减少PLTPO小鼠的动脉粥样硬化。的目标 本项目旨在进一步研究PLTP在BLp代谢中的作用， 动脉粥样硬化具体目标是：1）评估PLTP可能 在非脂蛋白产生模型中对BLp组装和分泌起作用 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 在肠细胞中BLp组装和分泌中的作用;以及3）确定 PLTPO小鼠中的抗动脉粥样硬化机制，而不是降低BLp。这个项目 将提供PLTP活性和BLp之间关系的新信息 生产，PLTP活性和动脉粥样硬化之间，并将进一步 评估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.