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）： 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，也有许多反应迟钝和不容忍的情况。因此，迫切需要降低血浆LDL的新方法，优选与他汀类药物协同作用。阻断肝脏VLDL（LDL的前体）分泌长期以来一直被认为是降低循环中LDL的有效替代方案。然而，这可能会产生不必要的后果，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是具有挑战性的，但具有很大的前景。针对这一建议所做的初步研究揭示了肝磷脂转移蛋白（PLTP）在调节VLDL分泌，从而调节血浆VLDL/LDL水平中的重要作用。然而，所涉及的机制仍不十分清楚。肝脏特异性PLTP表达（非过表达）/apoB 100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产生中起关键作用。我们的工作假设是：1）PLTP在细胞内VLDL脂化、转运和翻译后降解中起主要作用，从而促进VLDL的产生; 2）。细胞PLTP活性受多种因素的调控，弗林蛋白酶（furin，PCSK 3）就是其中之一。我们有两个具体目标。目的1：研究肝脏特异性PLTP活性对类人VLDL生成的影响。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)PLTP活性是VLDL转运囊泡（VTV）形成所必需的吗？和3）PLTP活性是否阻止VLDL在肝细胞中的降解。目的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，特别是其前段（profurin）在体内，并确定这种相互作用对活极低密度脂蛋白生产的影响。我们还将研究为什么profurin/PLTP介导的VLDL较少产生不会导致肝脏中的脂质蓄积。我们预计，这个项目将扩大我们的PLTP和弗林蛋白酶生物学的理解，并提供证据的一种新的策略，降低血浆VLDL/LDL水平，将是有效的人类。