Preliminary Communication
Antidiabetic sulfonylureas modulate farnesoid X receptor activation and target gene transcription
Published Online:6 Apr 2010https://doi.org/10.4155/fmc.10.10
Abstract
Background: The sulfonylureas glibenclamide and glimepiride are oral antidiabetic drugs that stimulate insulin secretion by closing pancreatic ATP-dependent potassium channels. The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates the expression of several target genes involved in bile acid metabolism and lipid and glucose homeostasis. Methods: In this study we investigated the potential effects of sulfonylureas on the signaling of FXR using a reporter-gene assay, real-time qPCR and computational methods such as molecular docking and molecular dynamic simulations. Results: We demonstrate that glibenclamide and glimepiride modulate FXR activation in a reporter-gene assay and induce FXR target genes in HepG2 cells. Within the docking experiments and molecular dynamics simulation, we found glibenclamide interacting with the ligand-binding domain of FXR and with helix 12. Conclusion: Glibenclamide and glimepiride are potential ligands of FXR and modulate activation and signaling.
Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest
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