REGULATION OF HIGH DENSITY LIPOPROTEIN METABOLISM BY CHOLESTEROL AND FATTY ACIDS

胆固醇和脂肪酸对高密度脂蛋白代谢的调节

• 批准号: 6296631
• 负责人: RAYMOND E GARCIA
• 金额: $ 13.37万
• 依托单位: CALIFORNIA STATE UNIVERSITY LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6296631
• 关键词: SDS polyacrylamide gel electrophoresis; apolipoproteins; atherosclerosis; blood lipoprotein metabolism; cholesterol; chylomicrons; density gradient ultracentrifugation; dietary constituent; dietary lipid; enzyme activity; enzyme linked immunosorbent assay; fatty acids; gel filtration chromatography; hepatic lipase; high density lipoproteins; hypercholesterolemia; hyperlipoproteinemia; laboratory rabbit; lipoprotein lipase; nutrition related tag; statistics /biometry; very low density lipoprotein

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.

长期目标是确定生化机制， 哪些膳食因素调节动物血浆脂蛋白代谢 模型该实验室特别感兴趣的是， 胆固醇和膳食脂肪酸调节代谢的高 密度脂蛋白（HDL）。这些脂蛋白被认为是 抗动脉粥样硬化，因为它们可以从外周血中清除多余的胆固醇， 细胞和运输它通过循环系统作为胆固醇 酯进入肝脏并在那里降解。这种逆转胆固醇 转运过程在调节细胞内和血浆中起重要作用 胆固醇浓度，从而发展 动脉粥样硬化HDL和HDL胆固醇（HDL-C）浓度降低 在胆固醇喂养的兔子，但不改变无论是荷荷巴油-或 胆固醇+荷荷巴油喂养的兔子。建议的目标 研究计划是提供一个生物化学解释的减少， 高胆固醇喂养兔的HDL-C浓度和HDL-C的维持 胆固醇+荷荷巴油喂养的兔子中的高水平C。是我们 假设它是霍霍巴油中的脂肪酸成分，可能 二十碳烯酸（20：1），这是活性部分，它减少了 胆固醇中胆固醇酯转移蛋白（CETP）的活性 + 荷荷巴油喂养的兔子该假说预测，高CETP活性 降低HDL 2胆固醇浓度， 胆固醇+荷荷巴油喂养的兔中的低CETP活性增加 了本研究旨在验证这一观点的有效性。 假设，并提供一个生物化学解释， 膳食胆固醇和膳食胆固醇+荷荷巴的相反作用 油对HDL-C代谢的影响。研究项目的具体目标是：（一） 为了鉴定霍霍巴油的分子成分（蜡、酒精或脂肪 酸），改变胆固醇喂养的兔中HDL-C浓度，（ii） 确定CETP或酶的转移活性是否 肝脂肪酶（HL）或脂蛋白脂肪酶（LPL）活性变化 兔子喂食富含胆固醇的饮食或胆固醇+荷荷巴油， 丰富的饮食，和（iii）确定HDL亚类（HDL 1，HDL 2，HDL 3） 其胆固醇含量在胆固醇喂养的兔子中降低， 胆固醇增加+荷荷巴油喂养的兔子。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）浓度的HDL级分， 家兔饲喂正常兔饲料或添加1% 胆固醇或1%胆固醇+2%霍霍巴油或1%胆固醇+1% 霍霍巴油的酒精成分或1%胆固醇+1%脂肪酸 （ii）GETP，HL，和 LPL在兔子喂养这五个实验饮食，和（iii）总 这五种动物中家兔HDL亚类的胆固醇浓度 饮食组。如果荷荷巴油的脂肪酸部分是活性剂， 并调节CETP、HL或LPL的活性， 将建立反应的脂肪酸特异性。如果不 改变它们的活性，那么它对酶活性的影响 将测试卵磷脂：胆固醇酰基转移酶（LCAT）。的 收集到的信息将用于制定一个机制， 解释膳食胆固醇和膳食胆固醇+ 荷荷巴油调节血浆中HDL-C的代谢，或提出一种 关于这些饮食因素如何调节HDL-C代谢的新假说。 了解饮食中的生物化学机制 胆固醇和膳食胆固醇+荷荷巴油调节新陈代谢 HDL和这些抗动脉粥样硬化脂蛋白中的胆固醇含量 将提高我们对饮食因素如何调节诱导的认识， 动脉粥样硬化的家兔，以及其可能的调节， 人类