Swertiamarin improves glucose and lipid metabolism disorders in T2DM via targeting FXR.

BACKGROUND: Glucose and lipid metabolism disorders are key features of type 2 diabetes mellitus (T2DM). Recent studies indicate that activating the bile acid nuclear receptor FXR can effectively enhance glucose and lipid metabolism in T2DM. Swertiamarin (STM), a compound from Swertia plants affects bile acid metabolism and has been shown to improve glucose and lipid metabolism in T2DM. However, its exact mechanism is unclear. Considering the influence of STM on bile acid metabolism, it is pertinent to investigate whether its therapeutic effects in T2DM are associated with the FXR. PURPOSE: This study focuses on the FXR target to explore the mechanism of STM in improving glucose and lipid metabolism disorders in T2DM. METHODS: C57BL/6 mice were administered streptozotocin (STZ) and placed on a high-fat diet to establish an in vivo model, while HepG2 cells were treated with palmitic acid (PA) to create an in vitro model for investigating the effects of STM on T2DM and FXR. Additionally, the study aimed to examine the mediating role of FXR in ameliorating glucose and lipid metabolism disorders in STM by interfering with FXR in a cellular model. To further explore the interaction between STM and FXR, the study utilized Cellular Thermal Shift Assay (CETSA), site-directed mutagenesis, Drug Affinity Responsive Target Stability (DARTS), and MicroScale Thermophoresis (MST) analyses. RESULTS: These results showed that STM can effectively improve metabolism disorders and reverse the changes in downstream pathways of FXR, such as sterol regulatory element-binding protein-1c (SREBP-1c), forkhead box protein O1 (FoxO1), and hepatocyte nuclear factor 4α (HNF-4α). In addition, in vitro interference with FXR can significantly reverse the regulatory effects of STM on SREBP-1c, FoxO1, and HNF-4α pathways. The compound-protein interaction assays, encompassing CETSA, DARTS, and MST, provided evidence that STM directly targets FXR. Furthermore, site-directed mutagenesis experiments identified Val-329, Asn-448, and Gln-400 as critical residues for this interaction. CONCLUSION: In summary, STM can target and active FXR to improve glucose and lipid metabolism disorder , thus playing a therapeutic role in T2DM.