Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPARγ-LXRα-ABCA1 pathway.
Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPARγ-LXRα-ABCA1 pathway.
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DOI：
10.1016/j.bbrc.2011.10.002
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发表时间：
2011-11
影响因子：
3.1
通讯作者：
Yanni Xu;F. Lai;Yang Xu;Ye-xiang Wu;Qi Liu;Ni Li;Yuzhen Wei;T. Feng;Zhihui Zheng;Wei Jiang;Liyan Yu;B. Hong;S. Si
中科院分区：
文献类型：
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作者：
Yanni Xu;F. Lai;Yang Xu;Ye-xiang Wu;Qi Liu;Ni Li;Yuzhen Wei;T. Feng;Zhihui Zheng;Wei Jiang;Liyan Yu;B. Hong;S. Si
ATP结合盒转运体A1（ABCA 1）促进胆固醇和磷脂从细胞流出到贫脂载脂蛋白A-I，在动脉粥样硬化中起重要作用。在先前的研究中，我们开发了一种高通量筛选方法，使用ABCA 1 p-LUC HepG 2细胞系来寻找ABCA 1的上调因子。在本研究中使用这种方法，我们发现麦考酚酸（MPA）上调ABCA 1表达（EC 50 =0.09μM）。MPA上调ABCA 1的表达，证实了实时定量逆转录-PCR和蛋白质印迹分析在HepG 2细胞。以前的工作表明MPA是过氧化物酶体增殖物激活受体γ（PPARγ; EC 50 =5.2-9.3μM）的有效激动剂。肝脏X受体α（LXRα）是PPARγ的靶基因，可直接调控ABCA 1的表达。Western blot分析显示MPA诱导HepG 2细胞LXRα蛋白表达。加入PPARγ拮抗剂GW 9662可显著抑制MPA诱导的ABCA 1和LXRα蛋白表达。这些数据表明MPA主要通过激活PPARγ来增加ABCA 1的表达。因此，MPA对ABCA 1表达上调的影响主要是由于激活了PPARγ-LXRα-ABCA 1信号通路。这是首次报道MPA抗动脉粥样硬化的作用机制。
ATP-binding cassette transporter A1 (ABCA1) promotes cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I and plays an important role in atherosclerosis. In a previous study, we developed a high-throughput screening method using an ABCA1p-LUC HepG2 cell line to find upregulators of ABCA1. Using this method in the present study, we found that mycophenolic acid (MPA) upregulated ABCA1 expression (EC50=0.09μM). MPA upregulation of ABCA1 expression was confirmed by real-time quantitative reverse transcription-PCR and Western blot analysis in HepG2 cells. Previous work has indicated that MPA is a potent agonist of peroxisome proliferator-activated receptor gamma (PPARγ; EC50=5.2–9.3μM). Liver X receptor α (LXRα) is a target gene of PPARγ and may directly regulate ABCA1 expression. Western blot analysis showed that MPA induced LXRα protein expression in HepG2 cells. Addition of PPARγ antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXRα protein expression. These data suggest that MPA increased ABCA1 expression mainly through activation of PPARγ. Thus, the effects of MPA on upregulation of ABCA1 expression were due mainly to activation of the PPARγ–LXRα–ABCA1 signaling pathway. This is the first report that the antiatherosclerosis activity of MPA is due to this mechanism.