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Regulation of ApoB Lipoprotein Expansion and Hepatic Lipid Efflux by ApoA-IV

ApoA-IV 对 ApoB 脂蛋白扩增和肝脂质流出的调节

基本信息

批准号：
9302519
负责人：
JOHN S PARKS
金额：
$ 38.75万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302519
关键词：
Acute Address Apolipoproteins A Apolipoproteins B Atherosclerosis Attenuated Body mass index Central obesity Characteristics Chylomicrons Cultured Cells Data Deposition Elasticity Engineering Epidemic Fatty Acids Fatty Liver Fatty acid glycerol esters Functional disorder Genes Goals Hepatic Hepatocyte High Fat Diet Histology Human Hyperglycemia Hypertriglyceridemia In Vitro Incidence Insulin Resistance Intracellular Transport Kinetics Length Link Lipids Lipoproteins Liver Mediating Membrane Messenger RNA Metabolic Metabolic syndrome Metabolism Modeling Mus Mutate Nuclear Obesity Orthologous Gene Particle Size Pathway interactions Perfusion Physiological Plasma Predisposition Process Production Proteins Proteolytic Processing Regulation Rodent Role Small Intestines System Testing Time Transgenic Mice Triglycerides Variant Very low density lipoprotein adenoviral-mediated apolipoprotein A-IV base in vivo lipid metabolism lipid transport mouse model non-alcoholic fatty liver nonalcoholic steatohepatitis overexpression particle programs public health relevance residence response trafficking transcription factor trend very low density lipoprotein triglyceride

项目摘要

DESCRIPTION (provided by applicant): An emerging trend suggests that apoB lipoprotein particle number, and not LDL- cholesterol, may best predict susceptibility to atherosclerotic cardiovascular disease (CVD). As very low density lipoprotein (VLDL) particle size is heterogeneous, reflecting the elasticity of the apoB lipoprotein assembly process, an unanswered question with relevance to many aspects of the metabolic syndrome is how the hepatocyte integrates particle number with particle size to achieve a given rate of hepatic lipid efflux. An overall goal of the current proposal is to explore the hypothesis that apolipoprotein A-IV (apoA-IV) is acutely regulated and serves an important role in hepatic lipid efflux by promoting nascent VLDL particle expansion. Defining this previously unknown role of apoA- IV in hepatic lipid metabolism and understanding the mechanism by which it functions has important translational potential, as it is likely that if VLDL-mediated lipid efflux could be achieved by a process of particle expansion at the expense of particle number, a less atherogenic lipoprotein profile may result, while still protecting the liver from steatosis. To explore and validate this hypothesis, three specific aims are proposed. Aim 1 will define the physiologic and pathophysiologic settings that regulate apoA-IV expressin in liver and will establish whether it is hepatic triglyceride (TG) acumulation that induces apoA-IV expression or whether the regulation of apoA-IV is linked to processes associated with enhanced assembly and secretion of VLDL. Aim 2 will establish the impact of apoA-IV on TG secretion and hepatic lipid content and pathophysiology. These studies are supported by preliminary data demonstrating that overexpression of apoA-IV in mouse liver both dramatically induces TG secretion and also dramatically reduces hepatic lipid burden. Finally, Aim 3 will focus on the mechanism by which apoA-IV promotes TG secretion and will explore the hypothesis that a direct-apoA-IV-apoB interaction alters the trafficking kinetics of apoB and promotes greater incorporation of lipid into nascent VLDL particles, while reducing total VLDL particle production.

描述（由申请人提供）：一种新兴趋势表明，apoB 脂蛋白颗粒数（而不是 LDL-胆固醇）可以最好地预测对动脉粥样硬化性心血管疾病 (CVD) 的易感性。由于极低密度脂蛋白 (VLDL) 颗粒大小不均匀，反映了 apoB 脂蛋白组装过程的弹性，因此与代谢综合征许多方面相关的一个未解答的问题是肝细胞如何将颗粒数量与颗粒大小结合起来以实现给定的肝脂质流出率。当前提案的总体目标是探索载脂蛋白 A-IV (apoA-IV) 受到急性调节并通过促进新生 VLDL 颗粒扩张在肝脂质流出中发挥重要作用的假设。定义apoA-IV在肝脏脂质代谢中的这种先前未知的作用并了解其发挥作用的机制具有重要的转化潜力，因为如果VLDL介导的脂质流出可以通过以牺牲颗粒数量为代价的颗粒扩张过程来实现，则可能会产生较少致动脉粥样硬化的脂蛋白谱，同时仍能保护肝脏免受脂肪变性。为了探索和验证这一假设，提出了三个具体目标。目标 1 将定义调节肝脏中 apoA-IV 表达的生理和病理生理环境，并将确定是否是肝脏甘油三酯 (TG) 积聚诱导了 apoA-IV 表达，或者 apoA-IV 的调节是否与增强 VLDL 组装和分泌相关的过程有关。目标 2 将确定 apoA-IV 对 TG 分泌和肝脂质含量以及病理生理学的影响。这些研究得到了初步数据的支持，表明小鼠肝脏中 apoA-IV 的过度表达既能显着诱导 TG 分泌，又能显着降低肝脏脂质负担。最后，目标 3 将重点关注 apoA-IV 促进 TG 分泌的机制，并将探讨 apoA-IV-apoB 直接相互作用改变 apoB 的运输动力学并促进脂质更多地掺入新生 VLDL 颗粒，同时减少 VLDL 颗粒总量的假设。