LIPID DETERMINANTS OF HIGH DENSITY LIPOPROTEIN (HDL) STRUCTURE

高密度脂蛋白 (HDL) 结构的脂质决定因素

• 批准号: 6242226
• 负责人: JOHN S PARKS
• 金额: $ 21.03万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242226
• 关键词: Cercopithecidae; Macaca fascicularis; apolipoproteins; atherosclerosis; biophysics; blood lipoprotein metabolism; calorimetry; chemical binding; circular dichroism; conformation; dietary lipid; disease /disorder model; gel electrophoresis; high density lipoproteins; immunoaffinity chromatography; lipid structure; liver metabolism; nuclear magnetic resonance spectroscopy; nutrition related tag; phosphatidylcholine sterol acyltransferase; protein structure; species difference; transcription factor; unsaturated fatty acids

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.

高密度脂蛋白 (HDL) 浓度呈负相关 人类和非人类灵长类动物患有冠心病。 我们建议 使用两种非人类灵长类动物，即反应过度的食蟹猴 猴子和反应低下的非洲绿猴，表现出低 分别与高血浆 HDL 浓度进行比较，以研究饮食- 引起 HDL 生物物理特性的变化，从而导致 血浆 HDL 亚组分的浓度和分布发生改变。 在 n-3 和 n-6 多不饱和膳食脂肪均可降低 HDL 相对于饱和脂肪的浓度。 此外，类型 膳食脂肪对 HDL 亚分数分布具有相反的影响 非洲绿猴；相对于饱和脂肪，n-6多不饱和脂肪 膳食脂肪增加，n-3 多不饱和脂肪降低 HDL 亚分数 中等尺寸和密度。 我们假设生物物理学 新生 HDL 颗粒上脂质表面的特性调节 血浆 HDL 亚组分的大小分布和浓度 对脱辅基蛋白结合和构象以及 LCAT 成熟的影响 新生 HDL 到成熟血浆 HDL。 这些生物物理特性包括 脱辅基蛋白构象的亲和力和能力、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 两种物种的血浆和肝灌注液 HDL 的特性 的猴子被喂食 4 种膳食脂肪。 不同类型的饮食 脂肪将使我们能够改变浓度、成分和 2种动物血浆和肝灌流液HDL的亚组分分布 血浆高密度脂蛋白水平不同的猴子。 我们随后将 研究 LCAT 诱导肝灌注液 HDL 向成熟血浆的成熟 HDL 定义肝灌注液 HDL 的重要生物物理特性 导致饮食引起的血浆高密度脂蛋白浓度变化， 组成和亚分数分布。 重组 HDL (rHDL) 将 模仿肝脏灌注液 HDL 的大小和成分，并且 将用作肝灌注液 HDL 的化学定义替代物。 LCAT 诱导 RHDL 成熟为球形“血浆样”HDL 进行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 颗粒异质性。 最后，单层研究将用于 定义影响脱辅基蛋白结合的特定表面特性和 HDL 上的构象，可能有助于观察到 HDL 颗粒 异质性。 该项目的结果应该会带来新的和 有关 HDL 颗粒生物物理方面的重要信息 影响HDL颗粒异质性的结构。 此外，我们将 了解非人类灵长类动物的膳食脂肪类型如何影响 血浆和肝灌流液 HDL 的生物物理特性及其 新生肝脏 HDL 成熟为成熟血浆 HDL。 结果来自 这项研究应该有助于更好地了解 HDL 代谢和 可用于做出更多有关饮食的国家决策 对有冠心病风险的个体进行治疗。