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

ABSTRACT: 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.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.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 ?mol/L. Furthermore, BBR (25 ?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.BBR is an inhibitor of FABP4 and a potential drug candidate for the treatment of type 2 diabetes and atherosclerosis.

SUBMITTER: Cai HY

PROVIDER: S-EPMC4651057 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

Cai Hai-yan HY Wang Ting T Zhao Jian-chun JC Sun Peng P Yan Gui-rui GR Ding Hai-peng HP Li Ying-xia YX Wang He-yao HY Zhu Wei-liang WL Chen Kai-xian KX

Acta pharmacologica Sinica 20130930 11

<h4>Aim</h4>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.<h4>Methods</h4>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 inhibi ...[more]

PMID: 24077632

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Project description:Aimdes-O-methyllasiodiplodin (DML) from Cerbera manghas has shown antagonistic activity against mineralocorticoid receptor (MR). Considering the involvement of MR in the insulin tolerance, we attempted to investigate the potential of DML in the treatment of type 2 diabetes mellitus (T2DM).MethodsSurface plasmon resonance (SPR) technology and reporter gene-based assays were used to study protein-small molecule interactions. HepG2 and 3T3-L1 cells were treated with H2O2 (0.2 mmol/L) or aldosterone (10 nmol/L) for 24 h. The expression of MR in the cells was downregulated with siRNA. The anti-inflammatory effect of the compound was evaluated, respectively. db/db mice were administered DML (30 mg·kg(-1)·d(-1)) for 4 weeks. Serum biochemical parameters and insulin sensitivity were examined. The expression levels of pro-inflammatory cytokines (MCP-1, TNF-? and IL-6) and ROS-related genes (NADPH p47 subunit and transcriptional factor PU.1) in adipose tissues and livers were analyzed using real-time RT-PCR.ResultsIn HepG2 and 3T3-L1 cells, both H2O2 and aldosterone markedly stimulates the expression of MCP-1, TNF?, IL-6, p47 and PU.1 genes. Co-treatment with DML (10 ?mol/L) significantly reduced the H2O2- or aldosterone-induced expression of these genes. SPR-based assay confirmed the antagonistic activity of DML against the interaction between SRC-1 and MR-LBD. Furthermore, DML decreased aldosterone-induced MR transcriptional activity in a dose-dependent manner. Downregulation of MR with siRNA in the cells prevented or significantly attenuated aldosterone-stimulated expression of these genes, whereas DML did no longer affect the expression of these genes except that of IL-6. Oral administration of DML effectively reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) in db/db mice. The treatment also rectified the expression of pro-inflammatory factor and ROS-related genes in db/db mice.ConclusionDML effectively lowers the blood glucose level in db/db mice possibly via ameliorating the expression of obesity-related pro-inflammatory cytokines, highlighting the potential of the marine natural product as a drug lead for the treatment of metabolic disorders.

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Dataset Information

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

Publications

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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