title: Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPARγ-LXRα-ABCA1 pathway.
abstract: 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.
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors: Yanni
authors: Y
authors: Xu
authors: Fangfang
authors: F
authors: Lai
authors: Yang
authors: Y
authors: Xu
authors: Yexiang
authors: Y
authors: Wu
authors: Qi
authors: Q
authors: Liu
authors: Ni
authors: N
authors: Li
authors: Yuzhen
authors: Y
authors: Wei
authors: Tingting
authors: T
authors: Feng
authors: Zhihui
authors: Z
authors: Zheng
authors: Wei
authors: W
authors: Jiang
authors: Liyan
authors: L
authors: Yu
authors: Bin
authors: B
authors: Hong
authors: Shuyi
authors: S
authors: Si
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D045744:Cell Line, Tumor; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D000071518:Liver X Receptors; D009173:Mycophenolic Acid / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C457499:2-chloro-5-nitrobenzanilide; C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000813:Anilides; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D009173:Mycophenolic Acid