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: 3779545
• 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/3779545
• 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; low density lipoprotein; receptor expression; stable isotope diagnosis; tissue /cell culture; transport proteins; very low density lipoprotein; young adult human (21-34)

The cholesterol ester transfer protein (CETP) transfers lipids such as cholesterol and triglycerides among apoB-containing lipoproteins (VLDL, LDL) and apoA-I-containing lipoproteins (HDL). Genetic deficiency of CETP causes low levels of apoB and LDL and high levels of apoA-I and HDL, and has been proposed to be a protective condition against the development of coronary heart disease. We intensively investigated the lipoprotein metabolism in two unrelated patients with CETP deficiency using both endogenous labeling with stable isotopes and exogenously labeled radiotracers. We established that the catabolic rates of both apoA-I and HDL-cholesterol ester were substantially slower than in normal subjects, accounting for their higher plasma 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. We also determined that the rate of conversion of VLDL to LDL is significantly delayed in CETP deficiency, resulting in markedly increased catabolism of VLDL before its conversion to LDL. This accounts for the low plasma levels of apoB and LDL cholesterol in these subjects. These combined results suggest that pharmacologic inhibition of CETP would be likely to delay catabolism of HDL and to cause metabolic channelling of VLDL to a degradation pathway rather than to LDL formation. 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. 56% of the subjects were women. Six of the subjects were Asian.

胆固醇酯转移蛋白（CETP）转移脂质， 在含载脂蛋白B的脂蛋白（VLDL， LDL）和含apoA-I的脂蛋白（HDL）。 遗传缺陷 CETP导致低水平的apoB和LDL以及高水平的apoA-I和HDL， 并被认为是一种保护性条件， 冠心病的发展。 我们深入调查了 两例无血缘关系的CETP缺乏症患者的脂蛋白代谢 使用稳定同位素的内源标记和外源标记 标记的放射性示踪剂。 我们确定了这两种动物的分解代谢率 apoA-I和HDL-胆固醇酯显著低于正常对照组 受试者，解释其较高的血浆水平。 这表明 胆固醇逆向转运在CETP缺乏症中可能实际上被延迟， 高水平的高密度脂蛋白可能通过不同的 机制我们还确定了VLDL转化为LDL的速率 在CETP缺乏症中明显延迟，导致明显 VLDL转化为LDL前的催化活性增加。 这占 这些受试者的血浆载脂蛋白B和低密度脂蛋白胆固醇水平较低。 这些综合结果表明，CETP的药理学抑制 可能会延迟高密度脂蛋白的分解， 将VLDL引导至降解途径而不是LDL 阵 已经开发了定量血浆中CETP活性的测定法。 这将允许对CETP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 CETP缺乏症载脂蛋白代谢的研究 以及其他高脂蛋白血症患者。 这些研究包括19至67岁的受试者。56%的 受试者为女性。其中6名受试者为亚洲人。