[摘要]：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 mu M). 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 (PPAR gamma; EC50 = 5.2-9.3 mu M). Liver X receptor alpha (LXR alpha) is a target gene of PPAR gamma and may directly regulate ABCA1 expression. Western blot analysis showed that MPA induced LXR alpha protein expression in HepG2 cells. Addition of PPAR gamma antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR alpha protein expression. These data suggest that MPA increased ABCA1 expression mainly through activation of PPAR gamma. Thus, the effects of MPA on upregulation of ABCA1 expression were due mainly to activation of the PPAR gamma-LXR alpha-ABCA1 signaling pathway. This is the first report that the antiatherosclerosis activity of MPA is due to this mechanism. (C) 2011 Elsevier Inc. All rights reserved.
