LOW DENSITY LIPOPROTEIN (LDL) METABOLISM IN NONHUMAN PRIMATE ATHEROSCLEROSIS

非人灵长类动脉粥样硬化中的低密度脂蛋白 (LDL) 代谢

• 批准号: 5214029
• 负责人: LAWRENCE L RUDEL
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5214029
• 关键词: Cercopithecidae; Macaca fascicularis; acetyl coA acetyltransferase; apolipoproteins; atherosclerosis; blood lipoprotein metabolism; cholesterol; coronary disorder; dietary lipid; disease /disorder model; esterification; high density lipoproteins; isolation perfusion; liver function; low density lipoprotein; low density lipoprotein receptor; nutrition related tag; sterol esterase; very low density lipoprotein

The hypothesis behind these studies is that the type of dietary fat influences atherosclerosis development through effects on LDL concentration and composition. To test this hypothesis, we will study two nonhuman primate species, the hyper-responsive cynomolgus monkey and the hypo-responsive African green monkey, fed cholesterol together with four different dietary fats [saturated, monounsaturated, polyunsaturated (n-6), and polyunsaturated (n-3)]. Measurements of plasma lipoproteins and hepatic cholesterol metabolism will be correlated with the extent and severity of coronary artery atherosclerosis. The plasma lipoprotein measurements to be made include cholesterol concentrations among classes, including LDL, HDL, and VLDL, concentrations of four apolipoproteins including apoA-I, apoA-II, apoB, and apoE, concentration of Lp(a), particle heterogeneity of LDL and HDL, and plasma cholesteryl esterification and transfer. To detect differences in the regulation of hepatic cholesterol metabolism that may be directly related to dietary modification of plasma LDL concentrations, we will measure hepatic lipoprotein and cholesterol secretion and cholesterol secretion into bile using the isolated, perfused liver. In addition, we will attempt to inhibit the cholesterol esterifying enzyme in the liver, acyl- CoA:cholesterol acyltransferase(ACAT), with specific compounds to determine the effects of this enzyme on lipoprotein particle cholesteryl ester and apoB secretion. Preliminary evidence suggests that this enzyme may be contributing cholesteryl esters to the LDL particle that increase its atherogenicity, and that some dietary fats, such as n-3 polyunsaturated fat, effectively decrease the activity of this enzyme thereby decreasing LDL atherogenicity. We will also measure the extent of cholesterol absorption in each of the animals and we will estimate the level of LDL receptor function in each of the animals with LDL turnover studies in vivo. With these measurements, we can document specific dietary effects on individual aspects of cholesterol metabolism. Each of these will then be correlated to the extent of coronary artery atherosclerosis in each of the animals. In this way, we will learn about specific aspects of lipoprotein metabolism that are correlated to atherosclerosis and are likely to play an important role in lipoprotein- mediated development of the disease. The perturbations induced by dietary fat and study of two different primate species should allow more sensitive detection of regulatory factors. Development of this information will assist in designing strategies for prevention and treatment of coronary heart disease in man, which is the overall goal of this research.

这些研究背后的假设是， 通过影响LDL影响动脉粥样硬化的发展 浓度和组成。 为了验证这一假设，我们将研究 两种非人灵长类物种，高反应食蟹猴和 低反应的非洲绿色猴子，被喂食胆固醇和 四种不同的膳食脂肪[饱和，单不饱和，多不饱和 (n-6)和多不饱和（n-3）]。 血浆脂蛋白的测量 肝胆固醇代谢与肝硬化程度相关， 冠状动脉粥样硬化的严重程度。 血浆脂蛋白 要进行的测量包括类别之间的胆固醇浓度， 包括LDL、HDL和VLDL，四种载脂蛋白的浓度 包括apoA-I、apoA-II、apoB和apoE，Lp（a）浓度， LDL和HDL的颗粒异质性以及血浆胆固醇 酯化和转移。 为了检测调节的差异， 肝脏胆固醇代谢可能与饮食直接相关 通过改变血浆LDL浓度，我们将测量肝脏 脂蛋白和胆固醇分泌以及胆固醇分泌到胆汁中 用的是离体灌注的肝脏 此外，我们将努力 抑制肝脏中的胆固醇分解酶， CoA：胆固醇酰基转移酶（ACAT），具有特异性化合物， 确定这种酶对脂蛋白颗粒胆固醇的影响 酯和apoB分泌。 初步证据表明这种酶 可能是胆固醇酯对LDL颗粒的贡献， 它的动脉粥样硬化性，以及一些膳食脂肪，如n-3 多不饱和脂肪，有效降低这种酶的活性 从而降低LDL致动脉粥样硬化性。 我们还将测量 胆固醇的吸收，我们将估计 每只LDL转换动物的LDL受体功能水平 体内研究。 通过这些测量，我们可以记录特定的 饮食对胆固醇代谢各个方面的影响。 每个 这些将与冠状动脉的范围相关， 动脉粥样硬化。 通过这种方式，我们将了解 脂蛋白代谢的特定方面， 动脉粥样硬化，并可能在脂蛋白中发挥重要作用， 介导疾病的发展。 引起的扰动 饮食脂肪和研究两种不同的灵长类动物物种应该允许更多的 调节因子的灵敏检测。 发展这一 信息将有助于制定预防战略， 治疗男性冠心病，这是总体目标 这项研究。