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

• 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
• 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

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）：一个新的趋势表明，载脂蛋白B脂蛋白颗粒数量，而不是LDL-胆固醇，可能是预测动脉粥样硬化性心血管疾病（CVD）易感性的最佳指标。由于极低密度脂蛋白（VLDL）的颗粒大小是不均匀的，反映了载脂蛋白B脂蛋白组装过程的弹性，与代谢综合征的许多方面相关的一个未回答的问题是肝细胞如何将颗粒数量与颗粒大小相结合，以达到给定的肝脂质流出率。目前的建议的总体目标是探讨假设载脂蛋白A-IV（apoA-IV）是急性调节，并通过促进新生VLDL颗粒扩张在肝脏脂质流出中发挥重要作用。定义apoA-IV在肝脏脂质代谢中的这种先前未知的作用并理解其发挥作用的机制具有重要的翻译潜力，因为很可能如果VLDL介导的脂质流出可以通过以颗粒数量为代价的颗粒膨胀过程来实现，则可以产生致动脉粥样硬化性较低的脂蛋白谱，同时仍然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。目的1将确定调节apoA-IV在肝脏中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）累积诱导apoA-IV表达，或者apoA-IV的调节是否与VLDL的增强组装和分泌相关的过程有关。目的2：研究apoA-IV对TG分泌、肝脏脂质含量及病理生理的影响。这些研究得到了初步数据的支持，表明小鼠肝脏中apoA-IV的过表达既显著诱导TG分泌，又显著降低肝脏脂质负荷。最后，目标3将集中于apoA-IV促进TG分泌的机制，并将探索直接apoA-IV-apoB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，同时减少总VLDL颗粒产生的假设。