APOLIPOPROTEIN METABOLISM IN CETP DEFICIENCY AND HYPERALPHALIPOPROTEINEMIA

CETP 缺乏和高α脂蛋白血症中的载脂蛋白代谢

• 批准号: 3843306
• 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/3843306
• 关键词: apolipoproteins; blood lipoprotein metabolism; cholesterol esters; familial hyperlipoproteinemia; high density lipoproteins; human middle age (35-64); human subject; inborn lipid /lipoprotein disorder; lipid transport; longevity; low density lipoprotein; receptor expression; stable isotope diagnosis; tissue /cell culture; transport proteins; young adult human (21-34)

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.

高脂蛋白血症的一个确定的遗传原因是缺乏 胆固醇酯转移蛋白（CETP） 使用内源性标记 用稳定同位素标记的氨基酸，我们确定， HDL载脂蛋白A-I和A-II的分解代谢率基本上 比正常人慢，解释了他们更高的水平。 这 这表明胆固醇的逆向转运实际上可能被延迟， CETP缺乏，高水平的HDL可能是保护性的， 不同的机制。 此外，低密度脂蛋白水平 (LDL)及其相关的载脂蛋白apoB显著低于 在这些患者中， 这是由于快速的 LDL apoB与正常值相比。 然而，来自CETP缺乏患者的LDL 在正常受试者中没有分解代谢得更快，这表明LDL 受体在这种情况下不受调节。 LDL受体增加 低水平LDL的表达可能是第二个因素， 在这种情况下可能的寿命。 HDL颗粒LpA-I和LpA-I：A-II分离自三名患者 CETP缺乏症，综合征。 颗粒 更大，更富含脂质，并含有大量富含apoE的 粒子 LpA-I：A-II颗粒具有较高的apoA-I与apoA-II的比率。 来自CETP缺陷受试者的LpA-I和LpA-I：A-II均具有较高的 与正常细胞相比，对Hep G2细胞具有亲和力，但结合能力较低 粒子 已经开发了定量血浆中CETP活性的测定法。 这将允许对CETP活动的影响进行详细评估 对HDL代谢的影响 正在进行的研究涉及进一步调查 CETP缺乏症和其他患者的载脂蛋白代谢 高脂蛋白血症 这些研究包括19至67岁的受试者。 60%的 受试者为女性。 其中4名受试者为亚洲人。