PLTP as a target for lowering VLDL production

PLTP 作为降低 VLDL 产生的目标

• 批准号: 9269453
• 负责人: XIAN-CHENG JIANG
• 金额: --
• 依托单位: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269453
• 关键词: Aging; Apolipoproteins B; Atherosclerosis; Binding; Biology; Blood Circulation; Cardiac; Cardiovascular Diseases; Cholesterol Homeostasis; Clinical Management; Diabetes Mellitus; Disease; Dyslipidemias; Epidemic; FURIN gene; Family; Framingham Heart Study; Health; Hepatic; Hepatocyte; Human; Human Genome; Insulin Resistance; Intracellular Transport; Investigation; Knowledge; LDL Cholesterol Lipoproteins; Length; Lipids; Lipoprotein (a); Lipoproteins; Liver; Mediating; Metabolic syndrome; Morbidity - disease rate; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathologic; Pathway interactions; Phospholipid Degradation Pathway; Phospholipid Transfer Proteins; Physiological; Plasma; Play; Polyubiquitination; Prevention; Production; Proprotein Convertases; Proteins; Regulation; Reporting; Research; Risk; Risk Factors; Role; Serum; Transport Vesicles; Very low density lipoprotein; Vesicle Transport Pathway; Veterans; Work; aging population; base; driving force; genome wide association study; in vivo; insight; lipid transport; member; mortality; multicatalytic endopeptidase complex; novel; novel strategies; overexpression; prevent; protein complex; protein degradation; protein expression; protein function; public health relevance

 DESCRIPTION (provided by applicant): Summary Hypercholesterinemia-mediated cardiovascular diseases can be treated by statins. However, there are many instances of unresponsiveness and intolerance. Thus, there is urgent need for new approaches to lower plasma LDL, preferably that act synergistically with statins. Blocking liver VLDL, the precursor of LDL, secretion has long been recognized as an effective alternative to lower LDL in the circulation. However, this can have unwanted consequences, such as lipid accumulation in the liver. Therefore, targeting VLDL secretion without causing lipid accumulation is challenging but has great promise. Preliminary studies done for this proposal have revealed an important role of liver phospholipid transfer protein (PLTP) in regulating VLDL secretion, and thereby plasma VLDL/LDL levels. However, the mechanism involved is still not quite clear. The establishment of liver-specific PLTP expression (not overexpression)/apoB100-only mice gives us a unique opportunity to evaluate whether liver-generated PLTP plays a critical role in human-like VLDL production. Our working hypotheses are 1) PLTP plays a major role in intracellular VLDL lipidation, transport, and post-translational degradation, thus promotin VLDL production; 2). Cellular PLTP activity can be tightly regulated by some factors, furin (PCSK3) is one of them. We have two specific aims. Aim 1: To investigate the effect of liver-specific PLTP activity on human-like VLDL production. We will attempt to answer the following questions: 1) Is PLTP activity required for the VLDL lipidation in hepatocytes? 2) Is PLTP activity required for VLDL transport vesicle (VTV) formation? And 3) Does PLTP activity prevent VLDL degradation in hepatocytes. Aim 2: To investigate the impact of furin-mediated PLTP regulation on VLDL production. We will characterize the interaction between PLTP and furin, in particular its pro-segment (profurin) in vivo, and determine the effect of such interaction on live VLDL production. We will also investigate why profurin/PLTP-mediated VLDL less production does not cause lipid accumulation in the liver. We anticipate that this project will broaden our understanding of both PLTP and furin biology and provide evidence for a novel strategy for lowering plasma VLDL/LDL levels that will be effective in humans.

 描述（由申请人提供）： 摘要 高胆固醇血症介导的心血管疾病可以通过他汀类药物治疗。然而，存在许多反应迟钝和不宽容的情况。因此，迫切需要降低血浆低密度脂蛋白的新方法，最好是与他汀类药物协同作用。长期以来，阻断肝脏 VLDL（LDL 的前体）分泌一直被认为是降低循环中 LDL 的有效替代方案。然而，这可能会产生不良后果，例如肝脏中的脂质积累。因此，靶向 VLDL 分泌而不引起脂质积累具有挑战性，但前景广阔。针对该提案所做的初步研究表明，肝磷脂转移蛋白 (PLTP) 在调节 VLDL 分泌以及血浆 VLDL/LDL 水平方面发挥着重要作用。然而，所涉及的机制仍不太清楚。肝脏特异性 PLTP 表达（非过度表达）/apoB100 小鼠的建立为我们提供了一个独特的机会来评估肝脏产生的 PLTP 是否在类人 VLDL 产生中发挥关键作用。我们的工作假设是 1) PLTP 在细胞内 VLDL 脂化、运输和翻译后降解中发挥重要作用，从而促进 VLDL 的产生； 2）。细胞PLTP活性可以受到一些因素的严格调控，弗林蛋白酶（PCSK3）就是其中之一。我们有两个具体目标。目标 1：研究肝脏特异性 PLTP 活性对类人 VLDL 产生的影响。我们将尝试回答以下问题：1）肝细胞中 VLDL 脂化是否需要 PLTP 活性？ 2) VLDL 转运囊泡 (VTV) 的形成是否需要 PLTP 活性？ 3) PLTP 活性是否可以阻止肝细胞中的 VLDL 降解。目标 2：研究弗林蛋白酶介导的 PLTP 调节对 VLDL 产生的影响。我们将表征 PLTP 和弗林蛋白酶之间的相互作用，特别是体内其前片段 (profurin)，并确定这种相互作用对活 VLDL 产生的影响。我们还将研究为什么 profurin/PLTP 介导的 VLDL 产生减少不会导致肝脏中脂质积累。我们预计该项目将拓宽我们对 PLTP 和弗林蛋白酶生物学的理解，并为降低血浆 VLDL/LDL 水平的新策略提供证据，该策略对人类有效。