Distinct cellular loci for the ABCA1-dependent and ABCA1-independent lipid efflux mediated by endogenous apolipoprotein E expression
Distinct cellular loci for the ABCA1-dependent and ABCA1-independent lipid efflux mediated by endogenous apolipoprotein E expression
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DOI：
10.1161/01.atv.0000193627.12516.1d
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发表时间：
2006-01-01
影响因子：
8.7
通讯作者：
Mazzone, T
中科院分区：
文献类型：
--
作者：
Huang, ZH;Fitzgerald, ML;Mazzone, T
目的：载脂蛋白E（apoE）和ABCA 1的巨噬细胞表达已被证明可以调节这些细胞的脂质流出，并在体内发挥重要的动脉粥样硬化保护作用。我们评估了apoE和ABCA 1调节细胞固醇efflux.Methods和结果之间的关系：ApoE介导的，但ABCA 1独立的，脂质流出证明在3个模型系统。首先，腺病毒介导的apoE在从ABCA 1（-/-）小鼠分离的真皮成纤维细胞中的表达显著增加固醇和磷脂流出。第二，人apoE在巨噬细胞系中的表达增加了固醇流出，并且这种流出的增加并没有通过抑制ABCA 1的表达而减少。第三，使用apoE小干扰RNA减少apoE表达显著减少了ABCA 1（-/-）小鼠腹腔巨噬细胞的固醇流出。载脂蛋白E介导的，但ABCA 1独立的，脂质流出可以区分从依赖于分泌的载脂蛋白E的细胞外积累的脂质流出，因为外源性细胞衍生的载脂蛋白E刺激流出，只有从细胞表达ABCA 1。甾醇外排通常是最高的细胞表达ABCA 1和载脂蛋白E，可能代表的总和ABCA 1依赖和独立的途径apoE介导的sterol efflux.Conclusions：ABCA 1表达是必需的apoE介导的外排时，内源性合成的apoE细胞外积累。然而，我们的研究结果，建立了一个ABCA 1独立的途径，需要细胞内合成和/或转运的载脂蛋白E的脂质流出。
Objective: Macrophage expression of both apolipoprotein E (apoE) and ABCA1 have been shown to modulate lipid efflux from these cells and to play an important atheroprotective role in vivo. We evaluated the relationship between apoE and ABCA1 for regulating cellular sterol efflux.Methods and Results: ApoE-mediated, but ABCA1-independent, lipid efflux was demonstrated in 3 model systems. First, adenoviral-mediated expression of apoE in dermal fibroblasts isolated from ABCA1(-/-) mice significantly increased both sterol and phospholipid efflux. Second, expression of human apoE in a macrophage cell line increased sterol efflux, and this increment in efflux was not reduced by suppressing ABCA1 expression. Third, reduction of apoE expression using an apoE small interfering RNA significantly reduced sterol efflux from ABCA1(-/-) mouse peritoneal macrophages. ApoE-mediated, but ABCA1-independent, lipid efflux could be differentiated from lipid efflux that was dependent on the extracellular accumulation of secreted apoE, because exogenous cell-derived apoE stimulated efflux only from cells expressing ABCA1. Sterol efflux was usually highest in cells expressing both ABCA1 and apoE, likely representing a summation of the ABCA1-dependent and -independent pathways for apoE-mediated sterol efflux.Conclusions: ABCA1 expression is required for apoE-mediated efflux when endogenously synthesized apoE accumulates extracellularly. Our results, however, establish the existence of an ABCA1-independent pathway for lipid efflux that requires the intracellular synthesis and/or transport of apoE.