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：
8772438
负责人：
JOHN S PARKS
金额：
$ 38.5万
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/8772438
关键词：
Address Adenoviruses Apolipoproteins A Apolipoproteins B Atherosclerosis Attenuated Body mass index Central obesity Characteristics Chylomicrons Cultured Cells Data Deposition Diet Elasticity Engineering Epidemic Fatty Acids Fatty Liver Fatty acid glycerol esters Functional disorder Genes Goals Hepatic Hepatocyte Histology Human Hyperglycemia Hypertriglyceridemia In Vitro Incidence Insulin Resistance Intracellular Transport Kinetics LDL Cholesterol Lipoproteins Length Link Lipid Mobilization Lipids Lipoproteins Liver Liver diseases 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 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）：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心血管疾病（CVD）的易感性。由于非常低密度的脂蛋白（VLDL）粒径是异质的，反映了APOB脂蛋白组装过程的弹性，这是一个与代谢综合征的许多方面相关的未解决的问题，是肝细胞与粒度与粒度相结合以实现给定hepatic hepatic shepatic shepatic lipid Efflux的粒径的弹性。当前建议的总体目标是探讨载脂蛋白A-IV（APOA-IV）急剧调节的假设，并通过促进新生VLDL颗粒的扩展在肝脂质外排起重要作用。定义Apoa-IV在肝脂质代谢中的这种未知的作用，并了解其功能具有重要的翻译潜力，因为如果VLDL介导的脂质流出可以通过粒子数量的颗粒膨胀过程来实现，那么粒子数量的费用，较小的颗粒型脂蛋白剖面可能会导致弱性脂肪蛋白概况，同时还可以保护脂肪蛋白。为了探索和验证这一假设，提出了三个具体目标。 AIM 1将定义调节肝脏中apoA-IV表达蛋白的生理和病理生理设置，并将确定是否诱导apoA-IV表达的是肝甘油三酸酯（TG）糖化剂是否与ApoA-IV的调节与与增强的组装和分泌VLDL相关的过程。 AIM 2将建立ApoA-IV对TG分泌和肝脂质含量和病理生理学的影响。这些研究得到了初步数据的支持，表明小鼠肝脏中apoA-IV的过表达均显着诱导TG分泌，并且大大减少了肝脂质负担。最后，AIM 3将重点放在APOA-IV促进TG分泌的机制上，并将探讨直接APOA-APOA-IV-APOB相互作用改变APOB的运输动力学的假设，并促进脂质在新生的VLDL颗粒中的更大融合，同时减少VLDL粒子的总生产。