title: IMB2026791, a xanthone, stimulates cholesterol efflux by increasing the binding of apolipoprotein A-I to ATP-binding cassette transporter A1.
abstract: It is known that the ATP-binding cassette transporter A1 (ABCA1) plays a major role in cholesterol homeostasis and high density lipoprotein (HDL) metabolism. Several laboratories have demonstrated that ABCA1 binding to lipid-poor apolipoprotein A-I (apoA-I) will mediate the assembly of nascent HDL and cellular cholesterol efflux, which suggests a possible receptor-ligand interaction between ABCA1 and apoA-I. In this study, a cell-based-ELISA-like high-throughput screening (HTS) method was developed to identify the synthetic and natural compounds that can regulate binding activity of ABCA1 to apoA-I. The cell-based-ELISA-like high-throughput screen was conducted in a 96-well format using Chinese hamster ovary (CHO) cells stably transfected with ABCA1 pIRE2-EGFP (Enhanced Green Fluorecence Protein) expression vector and the known ABCA1 inhibitor glibenclamide as the antagonist control. From 2,600 compounds, a xanthone compound (IMB 2026791) was selected using this HTS assay, and it was proved as an apoA-I binding agonist to ABCA1 by a flow cytometry assay and western blot analysis. The [3H] cholesterol efflux assay of IMB2026791 treated ABCA1-CHO cells and PMA induced THP-1 macrophages (human acute monocytic leukemia cell) further confirmed the compound as an accelerator of cholesterol efflux in a dose-dependent manner with an EC(50) of 25.23 μM.
authors.affiliation: China Institute of Medical Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tiantanxili #1, Beijing 100050, China. mystlumin@yahoo.com.cn
authors.forename: Jikai
authors.initials: J
authors.lastname: Liu
authors.forename: Zhongbing
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yanni
authors.initials: Y
authors.lastname: Xu
authors.forename: Tingting
authors.initials: T
authors.lastname: Feng
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Zhuorong
authors.initials: Z
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Hong
authors.forename: Zijian
authors.initials: Z
authors.lastname: Xie
authors.forename: Shuyi
authors.initials: S
authors.lastname: Si
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; C572849:IMB2026791; D011993:Recombinant Fusion Proteins; D044004:Xanthones; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D013755:Tetradecanoylphorbol Acetate; D005905:Glyburide