Journal
ACTA PHARMACOLOGICA SINICA
Volume 34, Issue 11, Pages 1397-1402Publisher
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2013.97
Keywords
benzbromarone; uricosuric drug; fatty acid-binding protein 4; adipocyte; diabetes; db/db mouse; molecular docking
Funding
- National Natural Science Foundation of China [20721003, 81072681]
- International ST Cooperation [2010DFB73280]
- National 863 High Performance Computing Project, China [2012AA01A305]
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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 mu mol/L. Furthermore, BBR (25 mu mol/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.
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