DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux-an LXR-dependent mechanism.
DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux-an LXR-dependent mechanism.
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DOI：
10.1016/j.bbalip.2013.02.007
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发表时间：
2013-06
期刊：
影响因子：
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通讯作者：
Ling Zhang;Meixiu Jiang;Yongsheng Shui;Yuanli Chen;Qixue Wang;Wenquan Hu;Xingzhe Ma;Xiaoju Li
中科院分区：
文献类型：
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作者：
Ling Zhang;Meixiu Jiang;Yongsheng Shui;Yuanli Chen;Qixue Wang;Wenquan Hu;Xingzhe Ma;Xiaoju Li
ATP结合盒转运蛋白A1（ABCA 1）促进胆固醇流出，从而抑制脂质负载的巨噬细胞/泡沫细胞形成和动脉粥样硬化。ABCA 1的表达受肝脏X受体（LXR）激活的转录调控。依托泊苷和替尼泊苷都是DNA拓扑异构酶II（Topo II）抑制剂，并且是用于治疗各种癌症的化疗药物。有趣的是，依托泊苷抑制兔动脉粥样硬化的机制尚不清楚。在此，我们报告了足叶乙甙和替尼泊甙对巨噬细胞ABCA 1表达和胆固醇流出的影响。足叶乙甙和替尼泊甙增加巨噬细胞游离胆固醇流出。这种增加与ABCA 1 mRNA和蛋白表达的增加有关。依托泊苷和替尼泊苷还以LXR依赖性方式增加ABCA 1启动子活性，并形成LXRE-LXR/RXR复合物，表明转录诱导已经发生。依托泊苷和替尼泊苷也诱导了ABCG 1和脂肪酸合成酶（FAS）的表达，这两个基因是LXR靶向的基因。在体内，给予小鼠依托泊苷或替尼泊苷诱导巨噬细胞ABCA 1表达，并增强胆固醇从巨噬细胞向粪便的逆向转运。总之，我们的研究表明，依托泊苷和替尼泊苷增加巨噬细胞ABCA 1表达和胆固醇流出，这可能归因于依托泊苷的抗动脉粥样硬化特性。我们的研究还描述了Topo II抑制剂除了在抗肿瘤发生中的作用之外的新功能。
ATP-binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux and thereby inhibits lipid-laden macrophage/foam cell formation and atherosclerosis. ABCA1 expression is transcriptionally regulated by activation of liver X receptor (LXR). Both etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors and are chemotherapeutic medications used in the treatment of various cancers. Interestingly, etoposide inhibits atherosclerosis in rabbits by unclear mechanisms. Herein, we report the effects of etoposide and teniposide on macrophage ABCA1 expression and cholesterol efflux. Both etoposide and teniposide increased macrophage free cholesterol efflux. This increase was associated with increased ABCA1 mRNA and protein expression. Etoposide and teniposide also increased ABCA1 promoter activity in an LXR-dependent manner and formation of the LXRE-LXR/RXR complex indicating that transcriptional induction had occurred. Expression of ABCG1 and fatty acid synthase (FAS), another two LXR-targeted genes, was also induced by etoposide and teniposide. In vivo, administration of mice with either etoposide or teniposide induced macrophage ABCA1 expression and enhanced reverse cholesterol transport from macrophages to feces. Taken together, our study indicates that etoposide and teniposide increase macrophage ABCA1 expression and cholesterol efflux that may be attributed to the anti-atherogenic properties of etoposide. Our study also describes a new function for Topo II inhibitors in addition to their role in anti-tumorigenesis.