GENETIC REGULATION OF LP(A) METABOLISM

Lp(A)是一种低密度脂蛋白样脂蛋白，与糖尿病的风险密切相关。 过早的动脉粥样硬化性心血管疾病。一种蛋白质，它 鉴定这种独特的脂蛋白为apo(A)，具有很高的同源性 用纤溶酶原。Apo(A)是多态的，有许多不同大小的 这种蛋白质在种群中。这种体型多态是由基因决定的 确定的，并反过来是血浆水平的主要决定因素 Lp(A)。我们之前证实，在拥有相同基因的个体 载脂蛋白(A)亚型但不同水平的Lp(A)，在生产中的变异 Lp(A)率是血浆Lp(A)水平变化的原因。更多 最近，我们对个体进行了一系列的动力学研究。 两种载脂蛋白(A)杂合子及其代谢率的直接比较 两种形式都存在于同一个体中。载脂蛋白(A)亚型的大小 不会影响其分解代谢率，而是其分解代谢率 制作。这为这种联系奠定了新陈代谢基础 载脂蛋白(A)亚型大小与血浆Lp(A)水平之间的关系，并引导人们注意 载脂蛋白(A)大小可能影响其比率的机制 生物合成。 关于低密度脂蛋白受体是否可能是 负责体内Lp(A)的分解代谢。我们对此进行了调查 通过研究Lp(A)在三例慢性阻塞性肺疾病患者中的分解代谢提出的问题 缺乏低密度脂蛋白受体的纯合子家族性高胆固醇血症。 在所有三名患者中，Lp(A)的分解代谢与 对照受试者，表明低密度脂蛋白受体在生理上 对Lp(A)分解代谢很重要。相反，血浆脂蛋白(A)水平升高 在纯合子FH中，Lp(A)的产生增加。 此外，在这些研究中，我们首次证明 一些Lp(A)在体内被转化为低密度脂蛋白，提供重要的信息 关于Lp(A)的代谢途径。 这些研究对象的年龄在19岁到74岁之间。45%的 受试者为女性。这些研究包括一名亚裔和两名西班牙裔 研究对象。

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.