Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.
Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.
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APOA1 的 C 末端翻转可促进小 HDL 依赖于 ABCA1 的胆固醇流出。
DOI：
10.1161/circulationaha.123.065959
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发表时间：
2024
期刊：
影响因子：
37.8
通讯作者：
H
中科院分区：
文献类型：
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作者：
He,Yi;Pavanello,Chiara;Hutchins,PatrickM;Tang,Chongren;Pourmousa,Mohsen;Vaisar,Tomas;Song,HyunD;Pastor,RichardW;Remaley,AlanT;Goldberg,IraJ;Costacou,Tina;SeanDavidson,W;Bornfeldt,KarinE;Calabresi,Laura;Segrest,JereP;H
胆固醇外排能力（CEC）预测心血管疾病独立于高密度脂蛋白（HDL）胆固醇水平。分离的小HDL颗粒是通过ABCA 1的巨噬细胞CEC的有效促进剂（ATP结合盒转运体A1）途径，但其机制尚不清楚.METHODSWe使用模型系统研究的重组HDL和血浆从控制和卵磷脂胆固醇酰基转移酶（LCAT）缺陷的主题，调查HDL颗粒的大小之间的关系，不同颗粒中APOA 1（载脂蛋白A1）的结构，以及血浆和分离的HDL的CEC。CEC随着粒径的减小而增大。化学交联肽的串联质谱分析和HDL的主要蛋白质APOA 1的分子动力学模拟表明，该蛋白质的C-末端的流动性明显较高，并在最小的颗粒中从表面翻转。为了探索模型系统研究的生理相关性，我们从LCAT缺陷受试者中分离出HDL，其小HDL（如重组HDL）是盘状的，由APOA 1、胆固醇和磷脂组成。尽管这些受试者的血浆HDL颗粒水平非常低，但CEC正常。在LCAT缺陷受试者和对照受试者中，分离的超小HDL（通过校准离子迁移率分析的超小和小HDL的混合物）的CEC比分离的较大尺寸的HDL大3至5倍。孵育LCAT缺陷的血浆和对照血浆与人LCAT转换超小和小HDL颗粒成较大的颗粒，它显着抑制CEC.CONCLUSIONSWe提出了一种机制，增强CEC的小HDL。在更小的颗粒中，APOA 1的2个反平行分子的C-末端从HDL的脂质表面“翻转”。这种延伸的构象允许它们与ABCA 1接合。相比之下，较大HDL的C-末端不能与ABCA 1有效地相互作用，因为它们形成了一个螺旋束，牢固地粘附在颗粒上的脂质上。增强CEC，如在较小颗粒中所见，预测心血管疾病风险降低。因此，超小和小HDL可能是HDL心脏保护作用的关键介质和指标。
BACKGROUNDCholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear.METHODSWe used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)–deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs.RESULTSWe quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometric analysis of chemically cross-linked peptides and molecular dynamics simulations of APOA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, whose small HDLs (like reconstituted HDLs) are discoidal and composed of APOA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC.CONCLUSIONSWe present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of APOA1 are “flipped” off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.