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

Molecules

Jikai Liu¹  Zhongbing Zhang¹  Yanni Xu¹  Tingting Feng¹  Wei Jiang¹  Zhuorong Li¹  Bin Hong¹  Zijian Xie¹ 

[1]¹China Institute of Medical Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tiantanxili #1, Beijing 100050, China[2] height:6px

[3]"> ²Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, OH 43614, USA[4] height:6px

[5]"> ^†These authors contributed equally to this work.

关键词: ABCA1;    regulator;    high-throughput screening;    xanthone;    anti-atherosclerosis agent;    cholesterol efflux;   

DOI  :  10.3390/molecules17032833

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.