LIPID DETERMINANTS OF HIGH DENSITY LIPOPROTEIN (HDL) STRUCTURE

高密度脂蛋白（HDL）浓度与 与人类和非人类灵长类动物的冠心病有关。 我们提出 使用两种非人类灵长类动物， 猴子和低反应的非洲绿色猴子，它们表现出低的 vs.高血浆HDL浓度，分别研究饮食- 诱导HDL的生物物理性质的变化， 改变血浆HDL亚组分的浓度和分布。 在 n-3和n-6两种多不饱和膳食脂肪均降低HDL 相对于饱和脂肪的浓度。 此外， 膳食脂肪对HDL亚组分分布有相反的影响， 非洲绿色猴;相对于饱和脂肪，n-6多不饱和脂肪 膳食脂肪增加和n-3多不饱和脂肪降低HDL亚组分 中等大小和密度的。 我们假设生物物理学 新生HDL颗粒上的脂质表面的性质调节 血浆HDL亚组分的大小分布和浓度 对载脂蛋白结合和构象以及对LCAT成熟的影响 新生HDL至成熟血浆HDL。 这些生物物理特性包括 对载脂蛋白构象、脂质流动性和 卵磷脂：胆固醇酰基转移酶（LCAT）反应性。 我们将测试我们的 假设首先定义饮食引起的生物物理变化， 来自两个物种的血浆和肝灌注液HDL的性质 的猴子喂养4种类型的膳食脂肪。 不同类型的饮食 脂肪将使我们能够改变浓度，成分， 两种动物血浆和肝脏灌流液HDL亚组分分布 血浆高密度脂蛋白水平不同的猴子。 然后我们将 研究LCAT诱导肝灌流液HDL成熟为成熟血浆 定义肝脏灌流液的重要生物物理特性 导致饮食诱导的血浆HDL浓度变化， 成分和亚馏分分布。 重组HDL（rHDL）将 模拟肝脏灌注液HDL的大小和组成， 将用作肝灌注液HDL的化学定义的替代物。 LCAT诱导RHDL成熟为球形“血浆样”HDL将 研究并与肝脏类似研究的结果进行比较 灌注HDL以阐明影响HDL的关键生物物理特性 颗粒不均匀性 最后，单层研究将用于 确定影响脱辅基蛋白结合的特定表面性质， 构象，并可能有助于观察到的HDL颗粒 异质性 该项目的成果将导致新的和 关于HDL颗粒生物物理学方面的重要信息 影响HDL颗粒异质性结构。 此外，我们将 了解非人类灵长类动物食用脂肪的类型如何影响 血浆和肝灌注液HDL的生物物理性质以及 新生肝HDL成熟为成熟血浆HDL。 的结果 这项研究将有助于更好地了解HDL代谢， 可以用来制定更多关于饮食的国家决策， 治疗有冠心病风险的个体。

High density lipoprotein (HDL) concentrations are inversely associated with coronary heart disease in human and nonhuman primates. We propose to use two species of nonhuman primates, the hyper-responding cynomolgus monkey and the hypo-responding African green monkey, which exhibit low vs. high plasma HDL concentrations, respectively, to study the diet- induced changes in the biophysical properties of HDL which result in altered concentration and distribution of plasma HDL subfractions. In both species n-3 and n-6 polyunsaturated dietary fat reduces HDL concentrations relative to saturated fat. In addition, the type of dietary fat has opposing effects on HDL subfraction distribution in African green monkeys; relative to saturated fat, n-6 polyunsaturated dietary fat raises and n-3 polyunsaturated fat lowers HDL subfractions of intermediate size and density. We hypothesize that the biophysical properties of the lipid surface on nascent HDL particles modulates the size distribution and concentration of plasma HDL subfractions through effects on apoprotein binding and conformation and on LCAT maturation of nascent HDL to mature plasma HDL. These biophysical properties include affinity and capacity for apoprotein conformation, lipid fluidity and lecithin:cholesterol acyltransferase (LCAT) reactivity. We will test our hypothesis by first defining the diet-induced changes in the biophysical properties of plasma and liver perfusate HDL derived from both species of monkeys fed 4 types of dietary fat. The different types of dietary fat will allow us to modify the concentration, composition, and subfraction distribution of plasma and liver perfusate HDL in 2 species of monkeys that have contrasting levels of plasma HDL. We will then study the LCAT-induced maturation of liver perfusate HDL to mature plasma HDL to define the important biophysical properties of liver perfusate HDL that result in the diet-induced changes in plasma HDL concentration, composition, and subfraction distribution. Recombinant HDL (rHDL) will be made which mimic the size and composition of liver perfusate HDL and will be used as chemically-defined surrogates of liver perfusate HDL. The LCAT induced-maturation of RHDL to spherical "plasma like" HDL will be studied and compared with results from similar studies with liver perfusate HDL to elucidate key biophysical properties which affect HDL particle heterogeneity. Finally, monolayer studies will be used to define specific surface properties which affect apoprotein binding and conformation on HDL and may contribute to the observed HDL particle heterogeneity. The results from this project should lead to new and important information regarding the biophysical aspects of HDL particle structure which affect HDL particle heterogeneity. In addition, we will learn how the type of dietary fat fed to nonhuman primates influences the biophysical properties of plasma and liver perfusate HDL and the maturation of nascent liver HDL to mature plasma HDL. The results from this study should lead to a better understanding of HDL metabolism and could be used to make more national decisions concerning dietary treatment of individuals at risk for coronary heart disease.