STRUCTURE AND FUNCTION OF APOLIPOPROTEIN A-IV

描述(申请人摘要)：载脂蛋白A-IV(apo A-IV)是一个46kD的蛋白 哺乳动物肠道在脂肪过程中合成的血浆糖蛋白 吸收并结合到新生乳糜粒的表面。虽然 载脂蛋白A-IV与许多代谢过程有关，主要是 有证据表明，它的进化是为了在肠道脂肪中发挥特定的作用。 吸收。使用从表面活性剂借来的几种新方法 我们发现载脂蛋白A-IV具有动态的界面性质 最适合稳定表面张力和分子堆积在 脂类/水界面。因此我们假设载脂蛋白A-IV在 通过控制乳胶粒形成在生长阶段的特殊作用 在扩张的乳胶粒表面的脂类堆积密度，从而 调节细胞磷脂和胆固醇进入表面 最终，部分肠道胆固醇被吸收。这一假设 预测：1)人类载脂蛋白A-LV的多态改变其界面 性质会影响胆固醇流入脂质/水界面；2) 部分胆固醇吸收将受到肠道水平的调节 载脂蛋白A-LV转基因和基因敲除小鼠载脂蛋白A-IV的合成 载脂蛋白A-LV在胆固醇吸收中的表达将取决于脂肪酰基 从饮食中吸收的物种。为了研究这些假设，我们将：1)使用 检测人类遗传和重组载脂蛋白影响的物理技术 A-LV基因多态对其分子结构、界面性质和基因频率的影响 它与脂质表面相互作用的动力学；2)使用油滴张力计 乳胶微粒脂肪氧化的新型三维模型检测技术 载脂蛋白A-LV的界面性质如何调节胆固醇流入 3)利用载脂蛋白A-IV转基因和基因敲除小鼠 检查载脂蛋白A-LV表达、膳食脂肪酸和ACAT的影响 对肠道胆固醇吸收的活性。我们相信这些研究 将提供对载脂蛋白A-IV特定生物学功能的洞察，载脂蛋白A-IV是一种新的 大道研究胆固醇吸收的复杂过程，以及新的 载脂蛋白A-LV基因多态对生物学影响的相关知识 对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.