GENETIC REGULATION OF LPA METABOLISM

LPA 代谢的遗传调控

• 批准号: 3757642
• 负责人: D J RADER
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3757642
• 关键词: apolipoproteins; blood lipoprotein metabolism; familial hyperlipoproteinemia type II; human subject; human tissue; low density lipoprotein; protein isoforms; receptor

Lp(a) is an LDL-like lipoprotein which contains a unique apolipoprotein designated apo(a) which has a high structural homology with plasminogen. Increased plasma levels of Lp(a) are associated with an increased risk of premature cardiovascular disease. Apo(a) is polymorphic and there is a series of isoforms of the apolipoprotein in the plasma ranging in molecular weight from 400K to 600K. The size and plasma levels of Lp(a) are genetically determined. Metabolic studies in subjects with different isoforms and plasma levels of Lp(a) established that the size of the apo(a) isoform does not effect Lp(a) catabolic rate but rather the rate of synthesis of the individual isoform. The larger the size of isoform the lower the rate of synthesis. These results have established that the synthesis of apo(a) is the major determinant of the plasma levels of Lp(a) and that variations in rate of catabolism does not play a major role in determining plasma levels of Lp(a). The pathway for catabolism for Lp(a) has not been established and it has been controversial if the LDL receptor is important in Lp(a) metabolism. The role of the LDL receptor in Lp(a) catabolism has been analyzed using Lp(a) kinetics in patients with familial hypercholesterolemia (FH) who lack the LDL receptor. Lp(a)levels are elevated in FH and it has been proposed that this is due to delayed catabolism secondary to the LDL receptor defect. Studies on four FH patients revealed that the catabolism of radiolabeled Lp(a) was similar in control subjects and the four FH patients indicating that the LDL receptor does not play a major role in the catabolism of Lp(a). The increased plasma levels of Lp(a) are due to increased production. In addition, it was also demonstrated for the first time that there was conversion of Lp(a) to LDL in vivo indicating that some of the Lp(a) is converted to LDL in the normal metabolic pathway of Lp(a) metabolism. Study subjects were ages 19 to 74, and 45% of the subjects were females. The studies included one Asian and two Hispanic subjects.

Lp(A)是一种类低密度脂蛋白，含有一种独特的载脂蛋白 命名为apo(A)，它与纤溶酶原具有高度的结构同源性。 血浆Lp(A)水平升高与风险增加相关 早产儿心血管疾病。载脂蛋白(A)是多态的，而且 血浆中载脂蛋白的一系列异构体 分子量在400K到600K之间。脂蛋白(A)的大小和血浆水平 是由基因决定的。不同疾病受试者的代谢研究 Lp(A)的异构体和血浆水平确定了 载脂蛋白(A)亚型不影响Lp(A)分解代谢率，但影响Lp(A)分解代谢率 个体异构体的合成。异构体的大小越大 合成的速度就越慢。这些结果表明， 载脂蛋白(A)的合成是决定血浆载脂蛋白水平的主要因素 Lp(A)和分解代谢率的变化不起主要作用 在测定血浆脂蛋白(A)水平中的作用。 Lp(A)的分解代谢途径尚未建立，但它已经建立 低密度脂蛋白受体在脂蛋白(A)代谢中是否起重要作用一直存在争议。 分析了低密度脂蛋白受体在脂蛋白(A)分解代谢中的作用 家族性高胆固醇血症患者的Lp(A)动力学 缺乏低密度脂蛋白受体。脂蛋白(A)水平在FH中升高，并已 提出这是由于低密度脂蛋白继发的延迟分解代谢所致 感受器缺陷。对四名FH患者的研究表明， 放射性标记的Lp(A)在对照组中的分解代谢相似， 4例FH患者表明低密度脂蛋白受体不起主要作用 在Lp(A)分解代谢中的作用。血浆脂蛋白(A)水平升高 是由于产量增加所致。此外，它还展示了 首次在体内将Lp(A)转化为低密度脂蛋白 表明一些Lp(A)在正常情况下转化为低密度脂蛋白 Lp(A)代谢的代谢途径。 研究对象的年龄在19岁到74岁之间，其中45%的对象是女性。 这些研究包括一名亚裔和两名西班牙裔受试者。