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

描述（由申请人提供）：一种新的趋势表明，载脂蛋白b颗粒数量，而不是LDL-胆固醇，可能最好地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，反映了载脂蛋白ob脂蛋白组装过程的弹性，一个与代谢综合征许多方面相关的未解决的问题是肝细胞如何整合颗粒数量和颗粒大小以实现给定的肝脂外排率。本研究的总体目标是探索载脂蛋白A-IV （apoA-IV）是否受到急性调节，并通过促进新生VLDL颗粒扩张在肝脏脂质外排中发挥重要作用。确定apoA- IV在肝脏脂质代谢中的未知作用并了解其作用机制具有重要的翻译潜力，因为如果vldl介导的脂质外排可以通过牺牲颗粒数量的颗粒扩张过程来实现，那么可能会导致较少的动脉粥样硬化脂蛋白谱，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，并将确定是肝脏甘油三酯（TG）积累诱导apoA-IV表达，还是apoA-IV的调节与VLDL的增强组装和分泌相关的过程有关。目的2将建立apoA-IV对TG分泌和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apoA-IV在小鼠肝脏中过表达既能显著诱导TG分泌，又能显著减轻肝脏脂质负担。最后，Aim 3将关注apoA-IV促进TG分泌的机制，并探索apoA-IV-apoB直接相互作用改变apoB运输动力学的假设，并促进脂质更多地结合到新生VLDL颗粒中，同时减少VLDL颗粒的总产生。

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.