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Gentiopicroside ameliorates glucose and lipid metabolism in T2DM via targeting FGFR1

Zhanchi Xu1, Jucun Huang2, Min Wen3

  • 1National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratoty for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou 510801, China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology
|June 17, 2024
PubMed
Abstract

Insights

Gentiopicroside (GPS) targets fibroblast growth factor receptor 1 (FGFR1), activating metabolic pathways to improve type 2 diabetes (T2DM) glucose and lipid issues. This mechanism involves preventing FGFR1 degradation, enhancing FGF21 signaling for T2DM treatment.

Area of Science:

  • Pharmacology and Molecular Biology
  • Metabolic Disorders Research
  • Natural Product Chemistry

Background:

  • Fibroblast growth factor 21/fibroblast growth factor receptor 1 (FGF21/FGFR1) pathway suppression is key in type 2 diabetes mellitus (T2DM) progression.
  • Gentiopicroside (GPS), from Gentiana macrophylla Pall., shows potential for T2DM metabolic control, but its mechanism is unclear.

Purpose of the Study:

  • To investigate if GPS improves T2DM glucose and lipid metabolism by modulating the FGF21/FGFR1 pathway.
  • To confirm FGFR1 as a direct target of GPS.

Main Methods:

  • Utilized palmitic acid (PA)-induced HepG2 cells and db/db mice models.
  • Employed Cellular Thermal Shift Assay (CETSA) and Surface Plasmon Resonance (SPR) to analyze GPS-FGFR1 interaction.
  • Assessed activation of PI3K/AKT and AMPK pathways.

Main Results:

  • GPS activates PI3K/AKT and AMPK pathways, improving glucose and lipid metabolism in T2DM models.
  • FGFR1 depletion reversed GPS-induced pathway activation.
  • GPS directly binds FGFR1, preventing its degradation by NEDD4 and promoting FGF21 signaling.

Conclusions:

  • GPS targets FGFR1, activating PI3K/AKT and AMPK pathways.
  • This interaction is a crucial mechanism for GPS in treating T2DM.
  • GPS demonstrates therapeutic potential for T2DM by modulating FGF21/FGFR1 signaling.
Keywords:
FGF21/FGFR1 pathwayGentiopicrosideType 2 diabetes mellitus

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