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- Title
Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice.
- Authors
Cai, Hai-yan; Wang, Ting; Zhao, Jian-chun; Sun, Peng; Yan, Gui-rui; Ding, Hai-peng; Li, Ying-xia; Wang, He-yao; Zhu, Wei-liang; Chen, Kai-xian
- Abstract
Aim:Fatty acid-binding protein 4 (FABP4) plays an important role in maintaining glucose and lipid homeostasis. The aim of this study was to find new inhibitors of FABP4 for the treatment of type 2 diabetes.Methods:Human FABP4 protein was expressed, and its inhibitors were detected in 1,8-ANS displacement assay. The effect of the inhibitor on lipolysis activity was examined in mouse 3T3-L1 preadipocytes. The db/db mice were used to evaluate the anti-diabetic activity of the inhibitor. Molecular docking and site-directed mutagenesis studies were carried out to explore the binding mode between the inhibitor and FABP4.Results:From 232 compounds tested, benzbromarone (BBR), an old uricosuric drug, was discovered to be the best inhibitor of FABP4 with an IC50 value of 14.8 μmol/L. Furthermore, BBR (25 μmol/L) significantly inhibited forskolin-stimulated lipolysis in 3T3-L1 cells. Oral administration of BBR (25 or 50 mg/kg, for 4 weeks) dose-dependently reduced the blood glucose level and improved glucose tolerance and insulin resistance in db/db mice. Molecular docking revealed that the residues Ser55, Asp76, and Arg126 of FABP4 formed important interactions with BBR, which was confirmed by site-directed mutagenesis studies.Conclusion:BBR is an inhibitor of FABP4 and a potential drug candidate for the treatment of type 2 diabetes and atherosclerosis.
- Subjects
URICOSURIC agents; FATTY acid-binding proteins; BLOOD sugar; LABORATORY mice; BLOOD lipids; LIPOLYSIS; MOLECULAR docking
- Publication
Acta Pharmacologica Sinica, 2013, Vol 34, Issue 11, p1397
- ISSN
1671-4083
- Publication type
Article
- DOI
10.1038/aps.2013.97