DIETARY FATTY ACIDS EFFECT ON LIPOPROTEIN TRANSPORT

膳食脂肪酸对脂蛋白转运的影响

• 批准号: 2218663
• 负责人: DAVID K SPADY
• 金额: $ 19.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2218663
• 关键词: RNase protection assay; apolipoproteins; blood lipoprotein metabolism; blood lipoprotein transport; chemical chain length; cholesterol; cholesterol esters; dietary fiber; dietary lipid; gene expression; genetic transcription; hamsters; high density lipoproteins; liver metabolism; low density lipoprotein; messenger RNA; nuclear runoff assay; nutrient interaction; nutrition related tag; receptor; receptor expression; saturated fatty acids; steroid biosynthesis; unsaturated fatty acids; western blottings

Plasma levels of low density lipoprotein (LDL) and high density lipoprotein (HDL) are two of the factors considered most important in the genesis of atherosclerosis and coronary heart disease (CHD). The long-term goal of the proposed studies is to understand how dietary lipids, in particular saturated and unsaturated fatty acids, regulate plasma concentrations of LDL and HDL. The significance of the project is emphasized by the high prevalence of CHD, the extraordinary cost of treatment and the potential for prevention by dietary intervention. Utilizing the hamster as an animal model whose response to diet modification is similar to humans, we have shown that dietary lipids alter plasma LDL concentrations primarily by regulating receptor-dependent LDL uptake by the liver. Using quantitative techniques to measure lipoprotein transport and gene expression, one group of studies will determine the mechanisms whereby the major fatty acids present in western diets regulate receptor-dependent LDL uptake by the liver. The effect of chain-length on saturated fatty acid-induced alterations in LDL receptor gene expression will also be examined. We recently showed that changes in LDL receptor mRNA levels account for changes in hepatic LDL receptor activity when dietary coconut oil is replaced by safflower oil. If the major fatty acids present i n western diets are shown to regulate hepatic LDL receptor activity at the transcriptional level, the promoter sequences involved will be determined using adenovirus mediated transfer of LDL receptor promoter/reporter constructs into the liver in vivo. A second-group of studies will be undertaken to understand how specific components of the diet regulate plasma HDL concentrations in the hamster and, in turn, to determine if diet-induced changes in plasma HDL levels reflect changes in the rate of reverse cholesterol transport. The saturation kinetics of HDL apo AI transport will first be established in vivo. Having established the kinetics of HDL transport, studies will be undertaken to determine how specific dietary components regulate HDL apo AI and cholesteryl ester levels. Finally, studies will be carried out to investigate the relationship between diet-induced changes in plasma HDL concentrations and the flux of HDL cholesterol back to the liver and to determine if primary overexpression of apo AI results in mobilization of cholesterol from peripheral tissues and enhanced reverse cholesterol transport. Overall, these detailed quantitative studies will provide important new information on the molecular mechanisms whereby specific dietary components regulate the major transport processes that control plasma LDL and HDL levels.

血浆低密度脂蛋白 (LDL) 和高密度脂蛋白水平 脂蛋白（HDL）是被认为是最重要的两个因素 动脉粥样硬化和冠心病（CHD）的起源。长期来看 拟议研究的目标是了解膳食脂质如何在 特定的饱和和不饱和脂肪酸，调节血浆 LDL 和 HDL 的浓度。 该项目的意义在于 冠心病的高患病率强调了治疗费用高昂 治疗和饮食干预预防的潜力。 利用仓鼠作为动物模型，观察其对饮食的反应 修饰与人类相似，我们已经证明膳食脂质会改变 血浆 LDL 浓度主要通过受体依赖性 LDL 进行调节 被肝脏吸收。使用定量技术测量脂蛋白 运输和基因表达，一组研究将确定 西方饮食中存在的主要脂肪酸调节机制 肝脏对受体依赖性 LDL 的吸收。链长的影响 饱和脂肪酸诱导的 LDL 受体基因表达变化 也将受到审查。我们最近发现 LDL 受体的变化 mRNA 水平解释肝脏 LDL 受体活性的变化 食用椰子油被红花油取代。如果主要脂肪酸 存在于西方饮食中，可调节肝脏 LDL 受体 转录水平的活性，涉及的启动子序列 将使用腺病毒介导的 LDL 受体转移来确定 启动子/报告基因构建体进入体内肝脏。第二组 将进行研究以了解具体组成部分如何 饮食调节仓鼠血浆 HDL 浓度，进而 确定饮食引起的血浆高密度脂蛋白水平的变化是否反映了 胆固醇反向转运的速率。 HDL 的饱和动力学 apo AI运输将首先在体内建立。建立了 HDL 运输动力学，将进行研究以确定如何 特定的饮食成分调节 HDL apo AI 和胆固醇酯 水平。最后，将进行研究以调查 饮食引起的血浆 HDL 浓度变化与 HDL 胆固醇流回肝脏并确定是否为原发性 apo AI 的过度表达导致胆固醇从 外周组织和增强的反向胆固醇转运。全面的， 这些详细的定量研究将提供重要的新信息 特定饮食成分调节的分子机制 控制血浆低密度脂蛋白和高密度脂蛋白水平的主要运输过程。