LOW DENSITY LIPOPROTEIN (LDL) METABOLISM IN NONHUMAN PRIMATE ATHEROSCLEROSIS

这些研究背后的假设是，膳食脂肪的类型 通过对低密度脂蛋白的作用影响动脉粥样硬化的发展 专注度和成分。为了验证这一假设，我们将研究 两个非人类灵长类物种，高度反应的食蟹猴和 这只反应迟钝的非洲绿猴，与 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)]。血浆脂蛋白的测定 而肝脏的胆固醇代谢将与其程度和 冠状动脉粥样硬化的严重程度。血浆脂蛋白 要进行的测量包括不同类别的胆固醇浓度， 包括低密度脂蛋白、高密度脂蛋白和极低密度脂蛋白在内，四种载脂蛋白的浓度 包括apoA-I、apoA-II、apoB和apoE，Lp(A)浓度， 低密度脂蛋白和高密度脂蛋白的颗粒异质性与血浆胆固醇 酯化和转移。发现监管方面的差异 肝脏胆固醇代谢可能与饮食直接相关 修改血浆低密度脂蛋白浓度，我们将测量肝脏 脂蛋白和胆固醇分泌及胆汁中胆固醇分泌 使用分离的、灌流的肝脏。此外，我们还将尝试 抑制肝脏中的胆固醇酯化酶，酰基- 辅酶A：胆固醇酰基转移酶(ACAT)，与特定的化合物 测定该酶对脂蛋白颗粒胆固醇的影响 酯和载脂蛋白B的分泌。初步证据表明，这种酶 可能是导致低密度脂蛋白颗粒增加的胆固醇酯 它的致动脉粥样硬化作用，以及一些饮食脂肪，如n-3 多不饱和脂肪，有效降低这种酶的活性 从而降低低密度脂蛋白的致动脉粥样硬化能力。我们还将测量其程度 每只动物对胆固醇的吸收，我们将估计 每种低密度脂蛋白转换动物的低密度脂蛋白受体功能水平 活体研究。有了这些测量，我们可以记录特定的 饮食对胆固醇代谢个体方面的影响。每个人 其中的一部分将与冠状动脉的范围相关 每只动物的动脉粥样硬化。通过这种方式，我们将了解到 与脂蛋白代谢相关的特定方面 并可能在脂蛋白中发挥重要作用- 促成了疾病的发展。由微扰引起的扰动 饮食脂肪和对两个不同灵长类物种的研究应该允许更多 对调节因素的灵敏检测。这方面的发展 信息将有助于制定预防和预防战略 治疗人类冠心病，这是总的目标 这项研究的最新进展。

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.