PLTP as a target for lowering VLDL production

PLTP 作为降低 VLDL 产生的目标

• 批准号: 9129936
• 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/9129936
• 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; Life; Lipids; Lipoprotein (a); Lipoproteins; Liver; Mediating; Metabolic syndrome; Morbidity - disease rate; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathway interactions; 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; Veterans; Work; aging population; base; driving force; genome wide association study; in vivo; insight; 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.