Antidiabetic sulfonylureas modulate farnesoid X receptor activation and target gene transcription

作者：Steri Ramona; Kara Mahmut; Proschak Ewgenij; Steinhilber Dieter; Schneider Gi**ert; Schubert Zsilavecz Manfred^*

来源：Future Medicinal Chemistry, 2010, 2(4): 575-586.

DOI：10.4155/FMC.10.10

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.

• 出版日期2010-4