Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice.
OBJECTIVE
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.


CONCLUSIONS
BBR is an inhibitor of FABP4 and a potential drug candidate for the treatment of type 2 diabetes and atherosclerosis.
1] Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] Advanced Institute for Translational Medicine, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Hai-yan
HY
Cai
Ting
T
Wang
Jian-chun
JC
Zhao
Peng
P
Sun
Gui-rui
GR
Yan
Hai-peng
HP
Ding
Ying-xia
YX
Li
He-yao
HY
Wang
Wei-liang
WL
Zhu
Kai-xian
KX
Chen
D041721:3T3-L1 Cells; D000818:Animals; D001553:Benzbromarone / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors*; D005951:Glucose Tolerance Test; D006801:Humans; D020128:Inhibitory Concentration 50; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D014528:Uricosuric Agents / Q000008:administration & dosage / Q000494:pharmacology
D001786:Blood Glucose; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D014528:Uricosuric Agents; D001553:Benzbromarone