STRUCTURE AND FUNCTION OF APOLIPOPROTEIN A-IV

描述（申请人摘要）：载脂蛋白A-IV（apo A-IV）是一种46 Kd的 哺乳动物肠道在脂质代谢过程中合成的血浆糖蛋白 吸收并结合到新生乳糜微粒的表面。虽然 载脂蛋白A-IV与许多代谢过程有关， 有证据表明，它进化到在肠道脂质中发挥特定作用， 吸收利用从表面活性剂中借用的几种新方法， 工业上，我们发现apoA-IV具有动态界面性质 最适合稳定表面张力和分子堆积， 脂/水界面。因此，我们假设载脂蛋白A-IV发挥作用， 在乳糜微粒形成的生长阶段的特定作用，通过控制 在扩张的乳糜微粒表面的脂质堆积密度，从而 调节细胞磷脂和胆固醇到达表面 最终导致肠道胆固醇的部分吸收。这一假设 预测：1）人载脂蛋白A-IV的多态性改变其界面 性质将影响胆固醇流入脂质/水界面; 2） 部分胆固醇吸收将由肠内胆固醇水平调节。 apo A-IV转基因和敲除小鼠中apo A-IV的合成; 3） 载脂蛋白A-IV表达对胆固醇吸收的影响将取决于脂酰 从饮食中吸收的种类。为了实现这些假设，我们将：1）使用 研究人类基因和重组载脂蛋白影响的物理技术 A-IV多态性对其分子结构、界面性质和生物相容性的影响 其与脂质表面相互作用的动力学; 2）使用油滴张力计 技术作为乳糜微粒脂质化的新型三维模型， 载脂蛋白A-IV的界面性质如何调节胆固醇流入 扩增乳糜微粒表面; 3）使用apo A-IV转基因和敲除小鼠， 研究载脂蛋白A-IV表达、膳食脂肪酸和ACAT的影响， 对肠胆固醇吸收的活性。我们相信这些研究 将深入了解载脂蛋白A-IV的特定生物学功能，这是一种新的 研究胆固醇吸收的复杂过程的途径，以及新的 关于载脂蛋白A-IV遗传多态性相关生物学影响的知识 动脉粥样硬化性心血管疾病的饮食控制。

DESCRIPTION (Applicant's abstract): Apolipoprotein A-IV (apo A-IV) is a 46 Kd plasma glycoprotein that is synthesized by the mammalian intestine during lipid absorption and incorporated into the surface of nascent chylomicrons. Although apo A-IV has been implicated in many metabolic processes, a preponderance of evidence suggests that it evolved to play a specific role in intestinal lipid absorption. Using several novel approaches borrowed from the surfactant industry, we have found that apo A-IV possesses dynamic interfacial properties that are optimal for stabilizing surface tension and molecular packing at lipid/aqueous interfaces. We therefore hypothesize that apo A-IV plays a specific role in the growth stage of chylomicron formation by controlling the density of lipid packing at the expanding chylomicron surface, thereby modulating the access of cellular phospholipids and cholesterol to the surface and, ultimately, fractional intestinal cholesterol absorption. This hypothesis predicts that: 1) polymorphisms of human apo A-lV that alter its interfacial properties will affect cholesterol influx to lipid/aqueous interfaces; 2) fractional cholesterol absorption will be modulated by the level of intestinal apo A-IV synthesis in apo A-lV transgenic and knockout mice; 3) the impact of apo A-lV expression on cholesterol absorption will depend upon the fatty acyl species absorbed from the diet. To pursue these hypotheses we will: 1) use physical techniques to examine the impact of human genetic and recombinant apo A-lV polymorphisms on its molecular structure, interfacial properties, and the kinetics of its interaction with lipid surfaces; 2) use oil-drop tensiometer techniques as novel 3-dimensional models of chylomicron lipidation to examine how the interfacial properties of apo A-lV modulate cholesterol influx to the expanding chylomicron surface; 3) use apo A-IV transgenic and knock-out mice to examine the impact of apo A-lV expression, dietary fatty acids, and ACAT activity on intestinal cholesterol absorption. We believe that these studies will provide insight into the specific biological function of apo A-IV, a new avenue to examine the complex process of cholesterol absorption, and new knowledge on the biological impact of apo A-lV genetic polymorphisms relevant to the dietary control of atherosclerotic cardiovascular disease.