Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide
Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide
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DOI：
10.1194/jlr.m300358-jlr200
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发表时间：
2004-07-01
影响因子：
6.5
通讯作者：
Krieger, M
中科院分区：
文献类型：
--
作者：
Nieland, TJF;Chroni, A;Krieger, M
I型B类清道夫受体（SR-BI）和ABCA 1是结构上不同的细胞表面蛋白，其在HDL代谢中起关键作用。SR-BI是一种以高亲和力结合HDL的受体，并介导胆固醇酯从富含脂质的HDL到细胞的选择性脂质摄取和未酯化胆固醇从细胞流出到HDL。ABCA 1介导未酯化的胆固醇和磷脂从细胞流出至贫脂载脂蛋白A-I（apoA-I）。ABCA 1和其他ATP结合盒超家族成员的活性被药物格列本脲抑制，SR-BI介导的脂质转运被称为BLT的小分子抑制剂阻断。在此，我们发现一种BLT，[1-（2-甲氧基-苯基）-3-萘-2-基-脲]（BLT-4），以与其抑制SR-BI相似的效力（IC 50相似于55 -60 μ M）阻断ABCA 1介导的胆固醇流出至脂质贫乏的apoA-I。相反，格列本脲阻断SR-BI介导的选择性脂质摄取和流出的效力与其抑制ABCA 1的效力相似（IC 50类似于275 -300 μ M）。与BLT的情况一样，格列本脲增加了HDL与SR-BI结合的表观亲和力。BLT-4和格列本脲对SR-BI和ABCA 1的相互抑制提高了这些蛋白质在其脂质转运机制中可能共享相似或共同步骤的可能性。Nieland，T.J.F.，A. Chroni，M. L.菲茨杰拉德，Z.拉克萨Zannis，T. Kirchhausen和M.克里格小分子BLT-4和格列本脲对SR-BI和ABCA 1介导的胆固醇转运的交叉抑制
Scavenger receptor class B type I (SR-BI) and ABCA1 are structurally dissimilar cell surface proteins that play key roles in HDL metabolism. SR-BI is a receptor that binds HDL with high affinity and mediates both the selective lipid uptake of cholesteryl esters from lipid-rich HDL to cells and the efflux of unesterified cholesterol from cells to HDL. ABCA1 mediates the efflux of unesterified cholesterol and phospholipids from cells to lipid-poor apolipoprotein A-I (apoA-I). The activities of ABCA1 and other ATP binding cassette superfamily members are inhibited by the drug glyburide, and SR-BI-mediated lipid transport is blocked by small molecule inhibitors called BLTs. Here, we show that one BLT, [1-(2-methoxy-phenyl)-3-naphthalen-2-yl-urea] (BLT-4), blocked ABCA1-mediated cholesterol efflux to lipid-poor apoA-I at a potency similar to that for its inhibition of SR-BI (IC50 similar to55-60 muM). Reciprocally, glyburide blocked SR-BI-mediated selective lipid uptake and efflux at a potency similar to that for its inhibition of ABCA1 (IC50 similar to275-300 muM). As is the case with BLTs, glyburide increased the apparent affinity of HDL binding to SR-BI. The reciprocal inhibition of SR-BI and ABCA1 by BLT-4 and glyburide raises the possibility that these proteins may share similar or common steps in their mechanisms of lipid transport.-Nieland, T.J. F., A. Chroni, M. L. Fitzgerald, Z. Maliga, V. I. Zannis, T. Kirchhausen, and M. Krieger. Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide