APOLIPOPROTEIN METABOLISM IN CETP DEFICIENCY AND HYPERALPHALIPOPROTEINEMIA

已确定的高脂蛋白血症的遗传原因是缺乏 胆固醇酯转移蛋白(CETP)。使用内源性标签 通过用稳定同位素标记的氨基酸，我们证实了 高密度脂蛋白A-I和A-II的分解代谢率基本上是 比正常受试者慢，这是他们水平较高的原因。这 这表明胆固醇的反向转运实际上可能会延迟 CETP缺乏，高水平的高密度脂蛋白可能通过一种 不同的机制。此外，低密度脂蛋白水平 (低密度脂蛋白)及其相关载脂蛋白apoB，显著低于 这些患者都是正常的。这被发现是由于快速分解新陈代谢 低密度脂蛋白载脂蛋白B与正常比较。然而，来自CETP缺陷患者的低密度脂蛋白 在正常受试者体内分解速度不快，这表明低密度脂蛋白 在这种情况下，受体是不受调控的。低密度脂蛋白受体增加 低密度脂蛋白水平的表达可能是导致 在这种情况下看到的可能的寿命。 从三名患者中分离出高密度脂蛋白颗粒LPA-I和LPA-I：A-II 具有CETP缺乏症和综合特征。这些粒子是 更大、更富脂，并包含富含载脂蛋白E的人群 粒子。LPA-I：A-II颗粒的apoA-I与apoA-II的比率较高。 CETP缺乏者的LPA-I和LPA-I：A-II均高于CETP缺乏者 与正常Hep G2细胞的亲和力但结合能力降低 粒子。 建立了一种定量测定血浆CETP活性的方法。 这将允许对CETP活动的影响进行详细评估 关于高密度脂蛋白代谢的研究。正在进行的研究涉及对 CETP缺乏症患者及其他患者载脂蛋白的代谢 高脂蛋白血症。 这些研究对象的年龄在19岁到67岁之间。60%的 受试者为女性。其中四名受试者是亚洲人。

An established genetic cause of hyperalphalipoproteinemia is deficiency of the cholesterol ester transfer protein (CETP). Using endogenous labeling with amino acids labeled with stable isotopes, we established that the catabolic rates of HDL apolipoproteins A-I and A-II were substantially slower than in normal subjects, accounting for their higher levels. This suggests that reverse cholesterol transport may actually be delayed in CETP deficiency, and that the high levels of HDL may be protective by a different mechanism. In addition, levels of low density lipoproteins (LDL) and its associated apolipoprotein apoB, are significantly lower than normal in these patients. This was found to be due to rapid catabolism of LDL apoB compared with normal. However, LDL from a CETP deficient patient was not catabolized faster in normal subjects, suggesting that the LDL receptor is unregulated in this condition. Increased LDL receptor expression with low levels of LDL may be a second factor contribution to the possible longevity seen in this condition. The HDL particles LpA-I and LpA-I:A-II were isolated from three patients with CETP deficiency and comprehensively characterized. The particles are larger and more lipid-enriched, and contain a population of apoE-rich particles. LpA-I:A-II particles have a higher ratio of apoA-I to apoA-II. Both LpA-I and LpA-I:A-II from CETP deficient subjects have higher affinity but less binding capacity to Hep G2 cells compared with normal particles. An assay to quantitate CETP activity in the plasma has been developed. This will permit the detailed assessment of the influence of CETP activity on HDL metabolism. Ongoing studies involve further investigation into the metabolism of apolipoproteins in CETP deficiency and in other patients with hyperalphalipoproteinemia. These studies included subjects of age 19 to 67 years. 60% of the subjects were women. Four of the subjects were Asian.