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

• 批准号: 6455674
• 负责人: XIAN-CHENG JIANG
• 金额: $ 30.4万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6455674
• 关键词: adeno associated virus group; antiatherogenic agent; apolipoprotein B; apolipoprotein E; atherosclerosis; atherosclerotic plaque; blood lipoprotein biosynthesis; blood lipoprotein metabolism; chylomicrons; diabetes mellitus; genetically modified animals; high density lipoproteins; hyperlipidemia; immunoprecipitation; laboratory mouse; liver cells; low density lipoprotein receptor; obesity; phospholipids; plasma; tissue /cell culture; transfection /expression vector; very low density lipoprotein

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）：分泌物增加和更高的水平 含APOB的脂蛋白（BLP）是观察到血脂异常的主要原因 在家族性高脂血症中，肥胖和糖尿病。血浆磷脂转移 已知蛋白质（PLTP）介导BLP和BLP之间的磷脂转移 HDL在血管内代谢期间，以解决PLTP的可能作用 在血脂异常和动脉粥样硬化中，PLTP基因敲除（PLTPO）小鼠育成 具有不同的高脂菌株。在APOB转基因（APOBTG）和APOE中 敲除（APOE0）背景，PLTP缺陷导致生产降低 BLP的水平，明显降低了动脉粥样硬化。 BLP分泌是 PLTP缺陷小鼠的肝细胞减少，这种效果被取消 当PLTP重新引入腺病毒时。初步研究表明 PLTP在调节BLP的分泌方面的主要且出乎意料的作用。 BLP的生物合成是一个两步过程：APOB的初始脂质 发生在内质网中，需要 微粒体甘油三酸酯转移蛋白。理解不足，第二 步骤可能涉及在新生中添加进一步的脂质 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的第二个脂质步骤。初步的 研究还表明，APOB的产生不受LDL受体基因的影响 与LDLRO小鼠相比，敲除（LDLRO）/PLTPO小鼠，但动脉粥样硬化 病变大大降低，表明：1）PLTP对 BLP的产生可能需要存在功能性LDL受体，在 至少在肝脏中； 2）有一些未知因素，除了降低 BLP，参与PLTPO小鼠的动脉粥样硬化的减少。目标 该项目是为了进一步研究PLTP在BLP代谢和 动脉粥样硬化。具体目的是：1）评估PLTP可能的假设 在产生非脂蛋白的模型中在BLP组装和分泌中发挥作用 系统（由PLTP，APOB和MTP转染），原发性肝细胞和肝癌 细胞（肝样细胞）； 2）评估PLTP起作用的假设 在BLP组装和肠细胞中的分泌； 3）确定 PLTPO小鼠中的抗皮疗机制，而不是降低BLP。这个项目 将提供有关PLTP活动与BLP之间关系的新信息 PLTP活性和动脉粥样硬化之间的生产，并将进一步 评估PLTP作为治疗靶标。