EFFECTS OF DIETARY CHOLESTEROL ON LIPOPROTEIN METABOLISM

膳食胆固醇对脂蛋白代谢的影响

• 批准号: 3358897
• 负责人: RAMPRATAP S KUSHWAHA
• 金额: $ 24.93万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3358897
• 关键词: Cercopithecidae; adipose tissue; apolipoproteins; atherosclerosis; blood lipoprotein; blood lipoprotein metabolism; cardiovascular disorder epidemiology; cholesterol; cholesterol esters; chylomicrons; density gradient ultracentrifugation; dietary lipid; fasting; high density lipoproteins; lipoprotein lipase; liver metabolism; low density lipoprotein; messenger RNA; nutrition related tag; phosphatidylcholine sterol acyltransferase; receptor; saturated fat; tissue /cell culture; triglycerides; unsaturated fats; very low density lipoprotein

Our long term goal is to determine the metabolic and molecular mechanisms by which individuals in a population respond differently to dietary cholesterol and how dietary fat modulates this response. We hypothesize that dietary cholesterol interacts with type of fat in determining plasma lipoprotein variables in a given genetic background. We will test this hytpothesis in selectively bred high and low responding baboons. The first experiment will use a factorial design to determine the interactions of four levels of dietary cholesterol intake, two types of fat (saturated and unsaturated), and two genetic backgrounds (high and low responders) on plasma lipoprotein heterogeneity and concentrations, and on factors in plasma (lecithin cholesterol acyl transferase and cholesteryl ester transfer protein) and liver (mRNA for apoproteins and LDL receptor), that affect plasma lipoprotein concentrations. The second experiment, designed to determine mechanisms accounting for the effects abserved in the first experiment, will use high and low responding baboons maintained on two levels of cholesterol (high and low) with either saturated or unsaturated fat. In these we will measure cholesterol absorption and the synthesis and catabolic rates of apo-B in VLDL, LDL and their subfractions. Turnover rates of apo-AI will be measured to determine whether changes are due to synthesis or catabolism. The HDL metabolic variables and clearance of post-prandial lipoproteins will be correlated with each other and with activities of post-heparin plasma hepatic triglyceride (HTGL) and lipoprotein lipases (LPL) and mRNA for apo-AI and HTGL in liver and LPL in adipose tissues. Apo-E turnover studies will be conducted and the metabolic variables will be correlated with mRNA for apo-E in liver. We will determine whether triglyceride-rich lipoproteins induced by dietary cholesterol promote cholesterol ester synthesis in macrophages. Using primary cultures of baboon hepatocytes, we will study the interaction of chylomicron remnant and fasting lipoproteins with hepatocytes to determine how these lipoproteins affect lipid metabolism in the liver. Using hep G2 cells, we will investigate the down regulation of hepatic LDL receptor by the lipoproteins from high and low responding animals maintained on different diets. These studies will enable us to understand why some indiviuals are susceptible and others resistant to dietary cholesterol.

我们的长期目标是确定代谢和分子 群体中个体的反应机制 与膳食胆固醇的不同以及膳食脂肪的调节方式 这个回应。 我们假设膳食胆固醇相互作用 与脂肪类型一起确定血浆脂蛋白变量 鉴于遗传背景。 我们将在 选择性培育高反应和低反应狒狒。 第一个 实验将使用因子设计来确定 四种膳食胆固醇摄入水平的相互作用，两种类型 脂肪（饱和和不饱和）和两种遗传背景 （高反应者和低反应者）血浆脂蛋白异质性和 浓度以及血浆中的因子（卵磷脂胆固醇酰基 转移酶和胆固醇酯转移蛋白）和肝脏 （脱辅基蛋白和 LDL 受体的 mRNA），影响血浆 脂蛋白浓度。 第二个实验的目的是 确定解释观察到的影响的机制 第一个实验，将使用高反应和低反应的狒狒 维持两种胆固醇水平（高和低） 饱和或不饱和脂肪。 在这些中我们将测量 胆固醇的吸收及其合成和分解代谢率 VLDL、LDL 及其亚组分中的 apo-B。 周转率 将测量 apo-AI 以确定变化是否是由于 合成或分解代谢。 HDL 代谢变量和 餐后脂蛋白的清除率与 相互之间以及与肝素后血浆肝活性 甘油三酯 (HTGL) 和脂蛋白脂肪酶 (LPL) 以及 mRNA 肝脏中的 apo-AI 和 HTGL 以及脂肪组织中的 LPL。 载脂蛋白E 将进行营业额研究和代谢变量 与肝脏中 apo-E 的 mRNA 相关。 我们将 确定富含甘油三酯的脂蛋白是否由 膳食胆固醇促进胆固醇酯合成 巨噬细胞。 使用狒狒肝细胞的原代培养物，我们 将研究乳糜微粒残留物与禁食的相互作用 脂蛋白与肝细胞如何确定这些脂蛋白 影响肝脏的脂质代谢。 使用hep G2细胞，我们将 研究肝脏 LDL 受体的下调 来自高反应和低反应动物的脂蛋白维持在 不同的饮食习惯。 这些研究将使我们了解为什么 有些人对饮食很敏感，而另一些人则有抵抗力 胆固醇。