DIETARY FATTY ACIDS EFFECT ON LIPOPROTEIN TRANSPORT

血浆低密度脂蛋白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 动脉粥样硬化与冠心病的发病机制。长期的 这项拟议研究的目标是了解饮食中的脂质是如何 特别是饱和和不饱和脂肪酸，调节血浆 低密度脂蛋白和高密度脂蛋白的浓度。该项目的意义在于 CHD的高患病率强调了 通过饮食干预进行治疗和预防的可能性。 利用仓鼠作为饮食反应的动物模型 修饰与人类相似，我们已经证明饮食中的脂类会改变 血浆低密度脂蛋白浓度主要通过调节受体依赖性低密度脂蛋白 被肝脏摄取。用定量技术测定脂蛋白 运输和基因表达，一组研究将确定 西方饮食中的主要脂肪酸调节机制 肝脏对受体依赖性低密度脂蛋白的摄取。链长对链长的影响 饱和脂肪酸诱导低密度脂蛋白受体基因表达的改变 还将接受检查。我们最近发现，低密度脂蛋白受体的变化 肝组织低密度脂蛋白受体活性的变化与mRNA水平有关 食用椰子油被红花油取代。如果主要脂肪酸 目前在西方饮食中被证明调节肝脏低密度脂蛋白受体 转录水平的活性，涉及的启动子序列 将通过腺病毒介导的低密度脂蛋白受体转移来确定 启动子/报告基因在体内构建到肝脏中。第二组-- 将进行研究，以了解特定的组件是如何 饮食调节仓鼠的血浆高密度脂蛋白浓度，进而 确定饮食诱导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度。高密度脂蛋白的饱和动力学 载脂蛋白AI转运将首先在体内建立。在建立了 高密度脂蛋白转运的动力学，将进行研究以确定如何 特定膳食成分调节高密度脂蛋白、载脂蛋白AI和胆固醇酯 级别。最后，将进行研究，以调查 饮食诱导的血浆高密度脂蛋白浓度变化与 高密度脂蛋白胆固醇回流到肝脏并确定是否为原发性 载脂蛋白AI的过表达导致胆固醇从 外周组织和增强的反向胆固醇转运。总的来说， 这些详细的定量研究将提供重要的新信息 特定膳食成分调控的分子机制 控制血浆低密度脂蛋白和高密度脂蛋白水平的主要转运过程。

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.