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: 3858033
• 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/3858033
• 关键词: apolipoproteins; blood lipoprotein metabolism; cardiovascular disorder epidemiology; cholesterol esters; familial hyperlipoproteinemia; high density lipoproteins; human subject; inborn lipid /lipoprotein disorder; lipid transport; longevity; low density lipoprotein; stable isotope diagnosis; transport proteins

High density lipoproteins (HDL) have a strong inverse correlation with atherosclerotic cardiovascular disease, and members of kindreds with high levels of HDL (a condition termed hyperalphalipoproteinemia) appear to be protected from heart disease and have longevity. A major goal of this project is to understand the molecular and metabolic bases of hyperalphalipoproteinemia. One genetic cause of high HDL levels is deficiency of the cholesterol ester transfer protein (CETP). The metabolism of apolipoproteins in two Japanese patients, one female and one male, with this condition were studied using amino acids labeled with stable isotopes. Apolipoprotein (apo) A-1, the major HDL protein, was very slowly catabolized, explaining the high plasma levels of this protein. In contrast, apoA-11, another major HDL protein, had only slightly slower catabolism than normal, explaining its relatively normal plasma levels. Hence, deficiency of CETP has a selective effect on the metabolism of apoA-l but not apoA-ll; this may be linked to the longevity seen in these kindreds. In addition, levels of low density lipoproteins (LDL) are low in these patients. This was found to be due to rapid catabolism of LDL. Therefore, CETP deficiency significantly affects the metabolism of both HDL and LDL in an apparently favorable way. This lends support to the concept that inhibition of CETP may be clinically desirable.

高密度脂蛋白（HDL）与 动脉粥样硬化性心血管疾病，以及高血压患者 HDL水平（一种称为高脂蛋白血症的疾病）似乎是 防止心脏病和长寿。 一个主要目标是 项目是了解的分子和代谢基础， 高脂蛋白血症。 高HDL水平的一个遗传原因是 胆固醇酯转移蛋白（CETP）缺乏。 的 两名日本患者的载脂蛋白代谢，一名女性和一名男性 使用标记有 稳定同位素 载脂蛋白（apo）A-1，主要的HDL蛋白，非常 缓慢分解代谢，解释了这种蛋白质的高血浆水平。 在 相比之下，apoA-11，另一种主要的HDL蛋白， 比正常情况下更高，解释了其相对正常的血浆水平。 因此，缺乏CETP对代谢有选择性影响， apoA-I而不是apoA-II;这可能与这些人中所见的长寿有关。 金斯。 此外，低密度脂蛋白（LDL）水平低 在这些患者中。 这被发现是由于LDL的快速催化。 因此，CETP缺乏显著影响HDL和HDL的代谢。 和低密度脂蛋白的作用 这支持了这一概念 CETP的抑制在临床上可能是需要的。