Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Biochem Biophys Res Commun. 2011 Nov 4;414(4):779-82. doi: 10.1016/j.bbrc.2011.10.002. Epub 2011 Oct 7.
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=0.09 μM). 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=5.2-9.3 μM). 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.
三磷酸腺苷结合盒转运体 A1（ABCA1）促进细胞内胆固醇和磷脂向富含载脂蛋白 A-I 的脂质中转运，并在动脉粥样硬化中发挥重要作用。在之前的研究中，我们使用 ABCA1p-LUC HepG2 细胞系开发了一种高通量筛选方法，以寻找 ABCA1 的上调物。在本研究中，我们使用该方法发现霉酚酸（MPA）可上调 ABCA1 表达（EC50=0.09 μM）。MPA 通过实时定量逆转录-PCR 和 HepG2 细胞中的 Western blot 分析证实了 ABCA1 表达的上调。先前的工作表明，MPA 是过氧化物酶体增殖物激活受体γ（PPARγ；EC50=5.2-9.3 μM）的有效激动剂。肝 X 受体α（LXRα）是 PPARγ 的靶基因，可能直接调节 ABCA1 的表达。Western blot 分析表明，MPA 诱导 HepG2 细胞中 LXRα 蛋白表达。添加 PPARγ 拮抗剂 GW9662 可显著抑制 MPA 诱导的 ABCA1 和 LXRα 蛋白表达。这些数据表明，MPA 通过激活 PPARγ 增加 ABCA1 表达。因此，MPA 对 ABCA1 表达的上调作用主要归因于 PPARγ 的激活。因此，MPA 上调 ABCA1 表达的作用主要归因于激活 PPARγ-LXRα-ABCA1 信号通路。这是首次报道 MPA 的抗动脉粥样硬化活性归因于这种机制。
