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Molecules 2012, 17(3), 2833-2854; doi:10.3390/molecules17032833
Article

IMB2026791, a Xanthone, Stimulates Cholesterol Efflux by Increasing the Binding of Apolipoprotein A-I to ATP-Binding Cassette Transporter A1

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2,*  and 1,*
1 China Institute of Medical Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tiantanxili #1, Beijing 100050, China 2 Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, OH 43614, USA These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 1 December 2011 / Revised: 16 February 2012 / Accepted: 24 February 2012 / Published: 7 March 2012
(This article belongs to the collection Bioactive Compounds)
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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 EC50 of 25.23 μM.
Keywords: ABCA1; regulator; high-throughput screening; xanthone; anti-atherosclerosis agent; cholesterol efflux ABCA1; regulator; high-throughput screening; xanthone; anti-atherosclerosis agent; cholesterol efflux
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Liu, J.; Zhang, Z.; Xu, Y.; Feng, T.; Jiang, W.; Li, Z.; Hong, B.; Xie, Z.; Si, S. IMB2026791, a Xanthone, Stimulates Cholesterol Efflux by Increasing the Binding of Apolipoprotein A-I to ATP-Binding Cassette Transporter A1. Molecules 2012, 17, 2833-2854.

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