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.
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Acknowledgements
This work was supported by grants from National Natural Science Foundation of China (20721003 and 81072681), the International S&T Cooperation (2010DFB73280) and the National 863 High Performance Computing Project (2012AA01A305), China.
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Supplemental Table S1 and Figure S1 are available at the website of Acta Pharmacologica Sinica.
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Supplementary Table S1
Comparison of the predicted binding free energy of BBR and FABP4 (wild type/mutants) (DOC 326 kb)
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Cai, Hy., Wang, T., Zhao, Jc. et al. Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice. Acta Pharmacol Sin 34, 1397–1402 (2013). https://doi.org/10.1038/aps.2013.97
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DOI: https://doi.org/10.1038/aps.2013.97
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