METABOLISM OF APO-E-RICH HDL BY HEPATIC LIPASE

肝脂肪酶对富含 APO-E-HDL 的代谢

• 批准号: 2224134
• 负责人: B M WAITE
• 金额: $ 17.69万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2224134
• 关键词: Cercopithecidae; acyl group; apolipoproteins; blood lipoprotein metabolism; cholesterol; dietary lipid; enzyme activity; high density lipoproteins; human subject; hydrolysis; laboratory rat; lipolysis; lipoprotein lipase; liver cells; liver metabolism; male; membrane model; molecular film; nutrition related tag; phospholipids; saturated fat; tissue /cell culture; unsaturated fats

Cholesterol homeostasis in humans is essential to health; failure to regulate the balance of dietary cholesterol intake, cholesterol synthesis and cholesterol excretion as bile salts leads to hypercholesterolemia and atherosclerosis. Here we focus on the roles that the hepatic lipase (HL) and apoE-rich HDL play in the uptake of cholesterol by liver. Specifically, we postulate that this HDL particle is preferentially degraded by HL, a process that facilitates hepatic uptake of cholesterol from circulation for excretion. Our previous work has shown that the presence of apoE in model lipid systems and in HDL particles increases phospholipid (PL) hydrolysis 3-fold. Others have shown that hydrolysis of HDL-PL facilitates cholesteryl ester uptake by a nonendocytotic mechanism. To test our postulate we will use two general approaches: 1) We will study the hydrolysis of natural HDL particles from monkeys on atherogenic diets that vary in the type of dietary fat. This study, in collaboration with Dr. L. Rudel, will determine the effect of saturated, monounsaturated, and polyunsaturated fat on HDL particle composition and the ability of HL to attack natural HDL's of varying acyl and apoprotein content. We will then use HDL-like particles that model natural HDL substrates to better define the regulation of HL at the molecular level. These particles provide carefully controlled composition to determine the effect of lipid composition, particle size, and apoprotein content on lipid hydrolysis by HL. Concomitantly, we will use model monomolecular films of substrate by which we can carefully regulate the surface properties of the lipid film and study the mechanism of apoE activation. 2) We will determine the role HL plays in the uptake of HDL lipid by rat hepatocytes to better understand how apoE, HL, and the apoE receptor on liver cells interact in HDL metabolism. In this study we will test our hypothesis that apoE can interact with its receptor and with HL to effect HDL metabolism. We will also use monkey hepatocytes so that a single species is investigated and so that our studies with monkeys can be related to the atherogenic index found by Dr. Rudel. Together these studies will establish the mechanism of apoE regulation of HDL metabolism by HL and its role in lipid clearance by liver. In turn this will help elucidate the roles HL and apoE play in cholesterol homeostasis.

人类的胆固醇稳态对健康至关重要。无法 调节饮食胆固醇摄入，胆固醇合成的平衡 随着胆汁盐导致高胆固醇血症和 动脉粥样硬化。 在这里，我们关注肝脂肪酶（HL）的角色 肝脏摄入胆固醇，富含Apoe的HDL发挥作用。 具体而言，我们假设该HDL粒子优先 HL降解，该过程有助于肝摄取胆固醇 从排泄的循环中。 我们以前的工作表明 模型脂质系统中的APOE和HDL颗粒中的存在增加 磷脂（PL）水解3倍。 其他已经表明水解 HDL-PL的促进胆汁滴虫促进胆汁滴虫的摄取 机制。 为了测试我们的假设，我们将使用两种一般方法： 1）我们将研究从猴子上的天然HDL颗粒的水解 饮食脂肪类型各不相同的动脉粥样硬化饮食。 这项研究，在 与L. Rudel博士的合作将确定饱和的效果， HDL颗粒组成上的单不饱和和多不饱和脂肪 HL攻击自然HDL的能力不同 内容。 然后，我们将使用模拟天然HDL底物的HDL样颗粒 更好地定义了分子水平上HL的调节。 这些 颗粒提供仔细控制的组成，以确定 脂质成分，粒径和载脂蛋白含量对 HL的脂质水解。 同时，我们将使用单分子模型 我们可以仔细调节表面的底物膜 脂质膜的性质并研究APOE激活的机理。 2）我们将确定HL在大鼠吸收HDL脂质中的作用 肝细胞可以更好地了解APOE，HL和APOE受体在 肝细胞在HDL代谢中相互作用。 在这项研究中，我们将测试我们的 假设ApoE可以与其受体相互作用，并与HL相互作用以实现 HDL代谢。 我们还将使用猴子肝细胞，以便一个 研究物种，以便我们对猴子的研究可以 与Rudel博士发现的动脉粥样硬化指数有关。 这些研究将共同​​建立APOE调节的机理 HL的HDL代谢及其在肝脏脂质清除中的作用。 反过来 这将有助于阐明HL和APOE在胆固醇中的角色 稳态。