GENETIC REGULATION OF LP(A) METABOLISM

LP(A) 代谢的遗传调控

• 批准号: 3779550
• 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/3779550
• 关键词: atherosclerosis; blood lipoprotein metabolism; familial hyperlipoproteinemia type II; genetic polymorphism; genetic regulation; human subject; isomer; low density lipoprotein; receptor

Lp(a) is an LDL-like lipoprotein which is highly associated with risk of premature atherosclerotic cardiovascular disease. The protein which identifies this unique lipoprotein is apo(a), which has high homology with plasminogen. Apo(a) is polymorphic, with many different sizes of this protein in the population. This size polymorphism is genetically determined, and in turn, is a major determinant of the plasma level of Lp(a). We previously established that in individuals with the same apo(a) isoform but different levels of Lp(a), variation in the production rate of Lp(a) is the cause of the variation in plasma Lp(a) levels. More recently, we have performed a series of kinetic studies in individuals heterozygous for two forms of apo(a) and directly compared the metabolism of both forms in the same individuals. The size of the apo(a) isoform does not affect its catabolic rate, but rather the rate of its production. This establishes the metabolic basis for the association between apo(a) isoform size and plasma Lp(a) level, and directs attention to the mechanism by which the apo(a) size may affect its rate of biosynthesis. There has been controversy about whether the LDL receptor may be responsible for catabolism of Lp(a) in vivo. We investigated this question by studying the catabolism of Lp(a) in three patients with homozygous familial hypercholesterolemia (FH) who lack the LDL receptor. In all three patients, the catabolism of Lp(a) was similar to that in control subjects, indicating that the LDL receptor is not physiologically important for Lp(a) catabolism. Instead, elevated plasma levels of Lp(a) in homozygous FH were shown to be due to increased production of Lp(a). Furthermore, in these studies we demonstrated for the first time that some Lp(a) is converted in vivo to LDL, providing important information about the metabolic pathways of Lp(a). These studies included subjects of age 19 to 74 years. 45% of the subjects were women. The studies included one Asian and two Hispanic subjects.

Lp(a) 是一种 LDL 样脂蛋白，与以下风险高度相关： 过早发生动脉粥样硬化性心血管疾病。 其中蛋白质 鉴定出这种独特的脂蛋白是apo(a)，具有很高的同源性 与纤溶酶原。 Apo(a) 具有多态性，具有许多不同大小的 人群中存在这种蛋白质。 这种大小多态性是遗传性的 确定，反过来，是血浆水平的主要决定因素 Lp(a)。 我们之前已经确定，在具有相同特征的个体中 apo(a) 同工型，但 Lp(a) 水平不同，产量存在差异 Lp(a) 的比率是血浆 Lp(a) 水平变化的原因。 更多的 最近，我们对个体进行了一系列动力学研究 两种形式的 apo(a) 杂合并直接比较代谢 两种形式在同一个人身上。 apo(a) 同工型的大小 不影响其分解代谢速率，而是影响其分解代谢速率 生产。这为该关联建立了代谢基础 apo(a) 同工型大小和血浆 Lp(a) 水平之间的关系，并引起注意 apo(a) 大小可能影响其速率的机制 生物合成。 关于 LDL 受体是否可能具有作用一直存在争议。 负责体内 Lp(a) 的分解代谢。我们对此进行了调查 通过研究三名患有 Lp(a) 的患者的分解代谢来回答这个问题 缺乏 LDL 受体的纯合子家族性高胆固醇血症 (FH)。 在所有三名患者中，Lp(a) 的分解代谢与 对照受试者，表明 LDL 受体在生理上不存在 对于 Lp(a) 分解代谢很重要。相反，血浆 Lp(a) 水平升高 纯合子 FH 中的 Lp(a) 产量增加所致。 此外，在这些研究中我们首次证明 一些 Lp(a) 在体内转化为 LDL，提供重要信息 关于Lp(a)的代谢途径。 这些研究包括 19 岁至 74 岁的受试者。 45%的 受试者是女性。研究对象包括一名亚裔和两名西班牙裔 科目。