携带相似载脂蛋白AI突变（载脂蛋白AI米兰型和载脂蛋白AI巴黎型）的受试者中载脂蛋白AI和AII的代谢

Metabolism of apolipoproteins AI and AII in subjects carrying similar apoAI mutations, apoAI Milano and apoAI Paris.

作者信息

Perez-Mendez O, Bruckert E, Franceschini G, Duhal N, Lacroix B, Bonte J P, Sirtori C, Fruchart J C, Turpin G, Luc G

机构信息

Department of Atherosclerosis, SERLIA and INSERM U325, Institut Pasteur de Lille, 1, rue du Professeur Calmette, 59019, Lille, France.

出版信息

Atherosclerosis. 2000 Feb;148(2):317-25. doi: 10.1016/s0021-9150(99)00279-8.

DOI:10.1016/s0021-9150(99)00279-8

PMID:10657568

Abstract

ApoAI Milano (AI(M)) and apoAI Paris (AI(P)) are mutant forms of apoAI in which cysteine is substituted for arginine at residues 173 and 151 respectively leading to the formation of homodimers and heterodimers with apoAII. Heterozygous subjects with these mutants are characterized by low levels of plasma HDL cholesterol and apoAI. The present study analyzed the metabolism of the different complexes of apoAI in three subjects, two AI(M) and one AI(P), using a primed-constant infusion of trideuterated leucine. In AI(M) carriers, the mutant form was almost equally distributed in AI(M) dimer, AI(M):AII heterodimer and the monomer, whereas, in the AI(P) subject, the mutant apoAI was essentially in the apoAI(P):AII complex. Normal apoAI was low in the AI(M) subjects (20 and 16 mg/dl) but very low in the AI(P) subject (0.3 mg/dl). In the AI(M) subjects, the low levels of apoAI were due to a rapid catabolism with a normal synthetic rate. However, the apoAI kinetics were heterogeneous with a rapid catabolism of the AI(M):AII complex (FCR of 0.430 and 0.401 day(-1)) and the AI(M) monomer (FCR of 0.570 and 0.406 day(-1)) whereas the AI(M) dimer was catabolized slowly (FCR of 0.114 and 0. 118 day(-1)). In contrast, AI(P) was catabolized relatively slowly with a FCR of 0.263, 0.182 and 0.258 day(-1) for AI(P) homodimer, apoAI(P):AII heterodimer and AI(P) monomer. In the three subjects, normal apoAI was catabolized quickly, with an FCR of 0.805 and 0.601 day(-1) in AI(M) carriers and 0.526 day(-1) in the AI(P) carrier. Therefore, the low level of apoAI in the AI(P) carrier is caused by a low production rate of apoAI, particularly of normal apoAI. In conclusion, apoAI is kinetically heterogeneous in AI(M) and in AI(P) subjects. Moreover, the two mutations lead to significant differences in the kinetic behavior of mutant apoAI depending on its inclusion in its complexes.

摘要

载脂蛋白A-I米兰型（AI(M)）和载脂蛋白A-I巴黎型（AI(P)）是载脂蛋白A-I的突变形式，其中分别在第173位和第151位残基上半胱氨酸取代了精氨酸，导致与载脂蛋白A-II形成同二聚体和异二聚体。携带这些突变的杂合子受试者的特征是血浆高密度脂蛋白胆固醇和载脂蛋白A-I水平较低。本研究使用氘代亮氨酸的首剂-恒速输注法分析了三名受试者（两名AI(M)携带者和一名AI(P)携带者）中不同载脂蛋白A-I复合物的代谢情况。在AI(M)携带者中，突变形式几乎均匀分布于AI(M)二聚体、AI(M):A-II异二聚体和单体中，而在AI(P)受试者中，突变的载脂蛋白A-I主要存在于载脂蛋白AI(P):A-II复合物中。AI(M)受试者中正常载脂蛋白A-I水平较低（分别为20和16mg/dl），而在AI(P)受试者中极低（0.3mg/dl）。在AI(M)受试者中，载脂蛋白A-I水平低是由于分解代谢迅速而合成速率正常。然而，载脂蛋白A-I的动力学是异质性的，AI(M):A-II复合物（分解代谢率分别为0.430和0.401天⁻¹）和AI(M)单体（分解代谢率分别为0.570和0.406天⁻¹）分解代谢迅速，而AI(M)二聚体分解代谢缓慢（分解代谢率分别为0.114和0.118天⁻¹）。相比之下，AI(P)分解代谢相对缓慢，AI(P)同二聚体、载脂蛋白AI(P):A-II异二聚体和AI(P)单体的分解代谢率分别为0.263、0.182和0.258天⁻¹。在这三名受试者中，正常载脂蛋白A-I分解代谢迅速，AI(M)携带者的分解代谢率为0.805和0.601天⁻¹，AI(P)携带者为0.526天⁻¹。因此，AI(P)携带者中载脂蛋白A-I水平低是由于载脂蛋白A-I，尤其是正常载脂蛋白A-I的产生率低所致。总之，在AI(M)和AI(P)受试者中，载脂蛋白A-I在动力学上是异质性的。此外，这两种突变导致突变载脂蛋白A-I的动力学行为存在显著差异，这取决于其在复合物中的组成情况。