DIETARY FATTY ACIDS EFFECT ON LIPOPROTEIN TRANSPORT

血浆低密度脂蛋白（LDL）和高密度脂蛋白（HDL）水平 脂蛋白（HDL）是两个被认为是最重要的因素， 动脉粥样硬化和冠心病（CHD）的起源。长期 拟议研究的目标是了解膳食脂质， 特别是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 强调了冠心病的高患病率， 治疗和通过饮食干预预防的潜力。 利用仓鼠作为动物模型，其对饮食的反应 修改是类似于人类，我们已经表明，饮食脂质改变， 血浆LDL浓度主要通过调节受体依赖性LDL 由肝脏摄取。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 受体依赖性LDL被肝脏摄取。链长的影响 饱和脂肪酸诱导LDL受体基因表达的改变 也将被审查。我们最近发现LDL受体的变化 mRNA水平解释了肝脏LDL受体活性的变化， 食用椰子油由红花油代替。如果主要脂肪酸 西方饮食中存在的调节肝脏LDL受体 在转录水平上的活性，涉及的启动子序列 将使用腺病毒介导的LDL受体转移来测定 启动子/报告基因构建体在体内植入肝脏。第二组 将进行研究，以了解 饮食调节仓鼠的血浆HDL浓度，反过来， 确定饮食诱导的血浆HDL水平变化是否反映了 胆固醇逆向转运的速率。 HDL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 动力学的HDL运输，研究将进行，以确定如何 特定的饮食成分调节HDL、载脂蛋白AI和胆固醇酯 程度.最后，将进行研究，调查 饮食诱导的血浆HDL浓度变化与 高密度脂蛋白胆固醇流回肝脏，并确定是否主要 载脂蛋白AI的过度表达导致胆固醇从 外周组织和增强的胆固醇逆向转运。总体而言， 这些详细的定量研究将提供重要的新信息， 关于特定饮食成分调节 控制血浆LDL和HDL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.