普罗布考抑制ABCA1介导的细胞脂质释放

Favari E etal. Arterioscler Thromb Vasc Biol, 2004; 24(12):2345-50.Epub

目的：ATP结合盒转运体A1（ABCA1）能介导脂质从细胞释放到缺脂载脂蛋白。本文介绍普罗布考对ABCA1介导的脂质释放的作用。方法和结果：普罗布考能抑制可表达ABCA1的J774巨噬细胞内胆固醇释放达80％。在含B类I型清道夫受体不含ABCA1的Fu5AH 肝癌细胞内，普罗布考对胆固醇释放无此作用。普罗布考抑制正常人皮成纤维细胞的胆固醇释放，但不抑制丹吉尔（Tangier）患者的成纤维细胞的胆固醇释放。荧光共焦显微镜法和生物素测定证明普罗布考抑制ABCA1从J774细胞内移至血膜。普罗布考也抑制ABCA1结合的胆固醇氧化酶敏感的血膜区的形成。与对ABCA1移至血膜的抑制作用一致，普罗布考降低细胞表面的[125I]标记的载脂蛋白AI的特异结合。结论：普罗布考是一个有效的ABCA1介导的胆固醇释放的抑制剂，不影响B类I型清道夫受体介导的胆固醇释放。ABCA1移至血膜的抑制作用可以部分地解释所报道的普罗布考的体内降高密度脂蛋白作用。

Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2345-50. Epub 2004 Dec.
 
Probucol inhibits ABCA1-mediated cellular lipid efflux.

Favari E, Zanotti I, Zimetti F, Ronda N, Bernini F, Rothblat GH.

Department of Pharmacological and Biological Sciences and Applied Chemistry, University of Parma, Parma, Italy.

OBJECTIVE: ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of lipids from cells to lipid-poor apolipoproteins. In this article, we characterize the effect of probucol on cellular ABCA1-mediated lipid efflux. METHODS AND RESULTS: Probucol inhibited cholesterol efflux up to 80% in J774 macrophages expressing ABCA1. In Fu5AH hepatoma cells that contain scavenger receptor class B, type I, but not functional ABCA1, we observed no effect of probucol on cholesterol efflux. Probucol inhibited cholesterol efflux from normal human skin fibroblasts but not from fibroblasts from a Tangier patient. Fluorescent confocal microscopy and biotinylation assay demonstrated that in J774 cells probucol impaired the translocation of ABCA1 from intracellular compartments to the plasma membrane. Probucol also inhibited the formation of an ABCA1-linked cholesterol oxidase sensitive plasma membrane domain. Consistent with the inhibitory effect on ABCA1 translocation to the plasma membrane, probucol reduced cell surface-specific [125I]-labeled apolipoprotein-AI binding. CONCLUSIONS: We conclude that probucol is an effective inhibitor of ABCA1-mediated cholesterol efflux without influencing scavenger receptor class B type I-mediated efflux. The inhibition of ABCA1 translocation to the plasma membrane may in part explain the reported in vivo high-density lipoprotein-lowering action of probucol.

PMID: 15514211 [PubMed - in process]