Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice
Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice
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老牌促尿酸排泄药苯溴马隆在体外抑制人脂肪酸结合蛋白4并降低db/db小鼠血糖水平
DOI：
10.1038/aps.2013.97
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发表时间：
2013-11-01
影响因子：
8.2
通讯作者：
Chen, Kai-xian
中科院分区：
文献类型：
--
作者：
Cai, Hai-yan;Wang, Ting;Chen, Kai-xian
目的：脂肪酸结合蛋白4（FABP 4）在维持糖脂平衡中起重要作用。本研究旨在寻找新的FABP 4抑制剂，用于治疗2型糖尿病。方法：表达人FABP 4蛋白，采用1，8-ANS置换法检测其抑制剂。在小鼠3 T3-L1前脂肪细胞中检测抑制剂对脂解活性的影响。db/db小鼠用于评价抑制剂的抗糖尿病活性。结果：从232个化合物中筛选出最佳的FABP 4抑制剂苯溴马隆（benzbromarone，BBR），其IC 50值为14.8 μ mol/L。此外，BBR（25 μ mol/L）显着抑制毛喉素刺激的3 T3-L1细胞的脂解。口服BBR（25或50 mg/kg，持续4周）剂量依赖性地降低了db/db小鼠的血糖水平，改善了葡萄糖耐量和胰岛素抵抗。结论：BBR是FABP 4的抑制剂，是治疗2型糖尿病和动脉粥样硬化的潜在候选药物。
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.