Exchange of Apolipoprotein A-I between Lipid-associated and Lipid-free States A POTENTIAL TARGET FOR OXIDATIVE GENERATION OF DYSFUNCTIONAL HIGH DENSITY LIPOPROTEINS
Exchange of Apolipoprotein A-I between Lipid-associated and Lipid-free States A POTENTIAL TARGET FOR OXIDATIVE GENERATION OF DYSFUNCTIONAL HIGH DENSITY LIPOPROTEINS
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DOI：
10.1074/jbc.m109.098434
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发表时间：
2010-06-11
影响因子：
4.8
通讯作者：
Oda, Michael N.
中科院分区：
文献类型：
--
作者：
Cavigiolio, Giorgio;Geier, Ethan G.;Oda, Michael N.
胆固醇代谢的一个重要事件是载脂蛋白A-I （apoA-I）的细胞胆固醇外排，载脂蛋白A-I是高密度脂蛋白（HDL）的主要蛋白。无脂apoA-I是atp结合盒A1的首选底物，其促进动脉壁巨噬细胞泡沫细胞的胆固醇外排。然而，血浆中绝大多数apoA-I与HDL相关，无脂apoA-I的产生机制尚不清楚。在本研究中，我们使用荧光标记的apoA-I，在不同的脂质结合状态下表现出不同的荧光发射光谱，来建立apoA-I在脂质相关状态和无脂质状态之间转变的动力学。这种方法的特点是apoA-I在脂相关和无脂状态之间的自发和快速交换。相反，当HDL上的apoA-I与双功能试剂交联或被髓过氧化物酶氧化时，apoA-I交换动力学显著降低。我们的观察结果支持这样的假设，即髓过氧化物酶对apoa - 1的氧化损伤限制了apoa - 1以无脂形式从HDL中释放的能力。apoA-I交换反应的损害可能是HDL功能失调的一个特征，有助于减少atp结合盒a1介导的胆固醇外排和动脉粥样硬化。
An important event in cholesterol metabolism is the efflux of cellular cholesterol by apolipoprotein A-I (apoA-I), the major protein of high density lipoproteins (HDL). Lipid-free apoA-I is the preferred substrate for ATP-binding cassette A1, which promotes cholesterol efflux from macrophage foam cells in the arterial wall. However, the vast majority of apoA-I in plasma is associated with HDL, and the mechanisms for the generation of lipid-free apoA-I remain poorly understood. In the current study, we used fluorescently labeled apoA-I that exhibits a distinct fluorescence emission spectrum when in different states of lipid association to establish the kinetics of apoA-I transition between the lipid-associated and lipid-free states. This approach characterized the spontaneous and rapid exchange of apoA-I between the lipid-associated and lipid-free states. In contrast, the kinetics of apoA-I exchange were significantly reduced when apoA-I on HDL was cross-linked with a bi-functional reagent or oxidized by myeloperoxidase. Our observations support the hypothesis that oxidative damage to apoA-I by myeloperoxidase limits the ability of apoA-I to be liberated in a lipid-free form from HDL. This impairment of apoA-I exchange reaction may be a trait of dysfunctional HDL contributing to reduced ATP-binding cassette A1-mediated cholesterol efflux and atherosclerosis.