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

描述(由申请人提供)：一个新的趋势表明，apoB脂蛋白颗粒数量，而不是低密度脂蛋白-胆固醇，可能是最好的预测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)的颗粒大小是不均匀的，反映了apoB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悬而未决的问题是，肝细胞如何将颗粒数量与颗粒大小结合起来，以达到给定的肝脂流出速率。目前该方案的总体目标是探索载脂蛋白A-IV(apoA-IV)受到严格调控并通过促进新生极低密度脂蛋白颗粒扩张而在肝脏脂质外流中发挥重要作用的假说。确定apoA-IV在肝脏脂质代谢中的这一先前未知的角色并了解其功能机制具有重要的翻译潜力，因为如果VLDL介导的脂质外流可能通过以颗粒数量为代价的颗粒膨胀过程实现，则可能会导致较少的致动脉粥样硬化脂蛋白分布，同时仍然保护肝脏免受脂肪变性的影响。为了探索和验证这一假设，本文提出了三个具体目标。目的1将确定调节肝脏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)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建立载脂蛋白A-IV对甘油三酯分泌、肝脏脂质含量和病理生理的影响。这些研究得到了初步数据的支持，这些数据表明，apoA-IV在小鼠肝脏中的过表达既能显著诱导甘油三酯的分泌，又能显著降低肝脏的脂质负担。最后，目标3将侧重于apoA-IV促进TG分泌的机制，并将探索这样的假设，即直接-apoA-IV-apoB相互作用改变apoB的运输动力学，促进脂类更多地结合到新生的VLDL颗粒中，同时减少VLDL总颗粒的产生。

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.