Cyclosporine A and PSC833 inhibit ABCA1 function via direct binding
Cyclosporine A and PSC833 inhibit ABCA1 function via direct binding
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DOI：
10.1016/j.bbalip.2012.11.002
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Ueda, Kazumitsu
中科院分区：
文献类型：
--
作者：
Nagao, Kohjiro;Maeda, Minami;Ueda, Kazumitsu
ATP结合盒蛋白A1（ABCA 1）在高密度脂蛋白（HDL）的生成中起关键作用。然而，HDL形成的详细机制仍不清楚;为了揭示它，特异性阻断HDL形成每个步骤的化学物质将是有用的。环孢素A抑制ABCA 1介导的胆固醇流出，但尚不清楚这是否是通过抑制钙调磷酸酶介导的。我们分析了环孢素A和相关化合物对BHK/ABCA 1细胞中ABCA 1功能的影响。环孢素A、FK 506和吡美莫司以浓度依赖性方式抑制ABCA 1介导的胆固醇流出，IC 50分别为7.6、13.6和7.0 μ M。mTOR抑制剂雷帕霉素也抑制ABCA 1，IC 50为18.8 μ M。在BHK/ABCA 1细胞中，这些药物的主要靶点在低得多的浓度下被抑制，表明它们不参与。[H-3]环孢菌素A与纯化的ABCA 1的结合可以清楚地检测到。此外，非免疫抑制性环孢菌素PSC 833抑制ABCA 1介导的胆固醇流出，IC 50为1.9 μ M，并有效地与[H-3]环孢菌素A竞争结合ABCA 1。这些结果表明，环孢菌素A和PSC 833通过直接结合抑制ABCA 1，ABCA 1抑制剂PSC 833是进一步研究HDL形成的详细机制的优秀候选者。(C)2012爱思唯尔有限公司版权所有。
ATP-binding cassette protein A1 (ABCA1) plays a key role in generating high-density lipoprotein (HDL). However, the detailed mechanism of HDL formation remains unclear; in order to reveal it, chemicals that specifically block each step of HDL formation would be useful. Cyclosporine A inhibits ABCA1-mediated cholesterol efflux, but it is not clear whether this is mediated via inhibition of calcineurin. We analyzed the effects of cyclosporine A and related compounds on ABCA1 function in BHK/ABCA1 cells. Cyclosporine A, FK506, and pimecrolimus inhibited ABCA1-mediated cholesterol efflux in a concentration-dependent manner, with IC50 of 7.6, 13.6, and 7.0 mu M, respectively. An mTOR inhibitor, rapamycin also inhibited ABCA1, with IC50 of 18.8 mu M. The primary targets for these drugs were inhibited at much lower concentrations in BHK/ABCA1 cells, suggesting that they were not involved. Binding of [H-3] cyclosporine A to purified ABCA1 could be clearly detected. Furthermore, a non-immunosuppressive cyclosporine, PSC833, inhibited ABCA1-mediated cholesterol efflux with IC50 of 1.9 mu M, and efficiently competed with [H-3] cyclosporine A binding to ABCA1. These results indicate that cyclosporine A and PSC833 inhibit ABCA1 via direct binding, and that the ABCA1 inhibitor PSC833 is an excellent candidate for further investigations of the detailed mechanisms underlying formation of HDL. (C) 2012 Elsevier B.V. All rights reserved.