REGULATION OF HIGH DENSITY LIPOPROTEIN METABOLISM BY CHOLESTEROL AND FATTY ACIDS

长期目标是通过以下方式确定生化机制 哪些饮食因素调节动物的血浆脂蛋白代谢 模特们。实验室特别感兴趣的是如何饮食 胆固醇和膳食脂肪酸调节高脂血症的代谢 密度脂蛋白(HDL)。这些脂蛋白被认为是 抗动脉粥样硬化，因为它们能从外周清除多余的胆固醇 细胞，并以胆固醇的形式通过循环系统运输 酯到肝脏，在那里它被降解。这种反式胆固醇 转运过程在调节细胞内和血浆中起重要作用 胆固醇浓度，因此，发展的 动脉硬化。高密度脂蛋白和高密度脂蛋白(高密度脂蛋白-C)浓度下降 在胆固醇喂养的兔子身上，但荷荷巴油或霍霍巴油都不变 胆固醇+荷荷巴油喂兔。建议的目标是 研究计划是提供一种生化解释，以减少 高密度脂蛋白胆固醇在兔体内的浓度及其维持 C在高胆固醇+霍霍巴油喂养的兔子中处于高水平。这是我们的 假设它是霍霍巴油中的脂肪酸成分，可能 二十碳烯酸(20：1)，即活性部分，它降低了 胆固醇中胆固醇酯转运蛋白的活性 +荷荷巴油喂兔。该假说预测CETP的高活性 在胆固醇喂养的兔中，降低HDL2胆固醇浓度和 喂饲胆固醇+霍霍巴油的兔CETP活性降低 它。这项研究方案旨在检验这一点的有效性 假说，并为生物化学解释 膳食胆固醇和膳食胆固醇+荷荷巴的相反作用 油对高密度脂蛋白胆固醇代谢的影响。研究项目的具体目标是：(一) 鉴定霍霍巴油的分子成分(蜡、酒精或脂肪 酸)可改变胆固醇喂养兔的高密度脂蛋白-C浓度，(Ii) 测定CETP或酶的转移活性 肝脂酶(HL)和脂蛋白脂酶(LPL)活性的变化 兔子要么喂高胆固醇饮食，要么喂胆固醇+霍霍巴油- 丰富的饮食，以及(Iii)识别高密度脂蛋白亚类(HDL1、HDL2、HDL3) 他们的胆固醇含量在喂饲胆固醇的兔子中降低， 高胆固醇+荷荷巴油喂兔。这些目标将是 通过测量和比较(I)总胆固醇(游离 胆固醇+胆固醇酯)在高密度脂蛋白部分的浓度 兔饲喂正常的兔饲料或添加1%的饲料。 胆固醇或1%胆固醇+2%霍霍巴油或1%胆固醇+1% 荷荷巴油的酒精成分或1%胆固醇+1%脂肪酸 荷荷巴油组分14天，(Ii)GETP，HL，和 喂饲这五种实验饲料的兔的LPL，以及(Iii)总 这五种兔的高密度脂蛋白亚类中的胆固醇浓度 饮食团体。如果荷荷巴油的脂肪酸部分是活化剂 它调节CETP、HL或LPL的活性，然后进一步研究 将确定该反应的脂肪酸专一性。如果它不是 改变它们的活性，然后它对酶的活性的影响 卵磷脂：胆固醇酰基转移酶(LCAT)将被检测。这个 收集的信息将被用来制定一种机制 解释膳食胆固醇和膳食胆固醇+ 霍霍巴油调节血浆中高密度脂蛋白胆固醇的代谢或提出一种 关于这些饮食因素如何调节高密度脂蛋白胆固醇代谢的新假说。 对饮食的生化机制的理解 胆固醇和饮食胆固醇+霍霍巴油调节新陈代谢 这些抗动脉粥样硬化脂蛋白中的高密度脂蛋白和胆固醇含量 将提高我们对饮食因素如何调节诱导性的了解 兔动脉粥样硬化及其可能的调控机制 人类。

The long-term objectives are to determine the biochemical mechanisms by which dietary factors regulate plasma lipoprotein metabolism in animal models. The laboratory is particularly interested in how dietary cholesterol and dietary fatty acids regulate the metabolism of high density lipoproteins (HDL). These lipoproteins are believed to be antiatherogenic, because they remove excess cholesterol from peripheral cells and transport it through the circulatory system as cholesteryl esters to the liver where it is degraded. This reverse cholesterol transport process is important in regulating intracellular and plasma cholesterol concentrations and, thereby, the development of atherosclerosis. HDL and HDL cholesterol (HDL-C) concentrations decrease in cholesterol-fed rabbits, but do not change in either jojoba oil- or cholesterol + jojoba oil-fed rabbits. The objective of the proposed research plan is to provide a biochemical explanation for the reduction in HDL-C concentration in cholesterol-fed rabbits and the maintenance of HDL- C at high levels in cholesterol + jojoba oil-fed rabbits. It is our hypothesis that it is the fatty acid component in jojoba oil, possibly eicosenoate (20:1), that is the active moiety and that it decreases the activity of cholesterol ester transfer protein (CETP) in the cholesterol + jojoba oil-fed rabbit. The hypothesis predicts that a high CETP activity in the cholesterol-fed rabbit decreases HDL2 cholesterol concentration and a low CETP activity in the cholesterol + jojoba oil-fed rabbit increases it. This research proposal is designed to test the validity of this hypothesis as well as to provide a biochemical explanation for the opposing actions of dietary cholesterol and dietary cholesterol + jojoba oil on HDL-C metabolism. The specific aims of the research project are (i) to identify the molecular component of jojoba oil (wax, alcohol, or fatty acid) that alters HDL-C concentration in cholesterol-fed rabbits, (ii) to determine whether or not the transfer activity of CETP or the enzymatic activity of hepatic lipase (HL) or lipoprotein lipase (LPL) change in rabbits fed either a cholesterol-rich diet or a cholesterol + jojoba oil- rich diet, and (iii) to identify the HDL subclasses (HDL1, HDL2, HDL3) whose cholesterol contents decrease in cholesterol-fed rabbits and increase in cholesterol + jojoba oil-fed rabbits. These aims will be achieved by measuring and comparing (i) the total cholesterol (free cholesterol + cholesteryl ester) concentration in the HDL fraction of rabbits fed either a normal rabbit chow diet or one supplemented with 1% cholesterol or 1% cholesterol + 2% jojoba oil or 1% cholesterol + 1% alcohol component of jojoba oil or 1% cholesterol + 1% fatty acid component of jojoba oil for 14 days, (ii) the activity of GETP, HL, and LPL in rabbits fed these five experimental diets, and (iii) the total cholesterol concentration in the HDL subclasses of rabbits in these five dietary groups. If the fatty acid moiety of jojoba oil is the active agent and it regulates the activity of CETP, HL; or LPL, then future studies will establish the fatty acid specificity of the reaction. If it does not alter their activity, then its impact on the enzymatic activity of lecithin:cholesterol acyltransferase (LCAT) will be tested. The information collected will be used either to formulate a mechanism of action that explains how dietary cholesterol and dietary cholesterol + jojoba oil regulate the metabolism of HDL-C in the plasma or to propose a new hypothesis on how these dietary factors may regulate HDL-C metabolism. An understanding of the biochemical mechanisms by which dietary cholesterol and dietary cholesterol + jojoba oil regulate the metabolism of HDL and the cholesterol content in these anti-atherogenic lipoproteins would improve our knowledge of how dietary factors regulate the induction of atherosclerosis in the rabbit as well as its possible regulation in humans.