2. Academic Validation
  3. Gentiopicroside ameliorates glucose and lipid metabolism in T2DM via targeting FGFR1

Gentiopicroside ameliorates glucose and lipid metabolism in T2DM via targeting FGFR1

  • Phytomedicine. 2024 May 27:132:155780. doi: 10.1016/j.phymed.2024.155780.
Zhanchi Xu 1,  Jucun Huang 2,  Min Wen 3,  Xuting Zhang 3,  Dongxin Lyu 3,  Shanshan Li 3,  Haiming Xiao 3,  Min Li 4,  Cuangpeng Shen 5,  Heqing Huang 6
Affiliations

Affiliations

  • 1 National-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.
  • 2 Hubei NO.3 People's Hospital of Jianghan University, Wuhan 430033, China.
  • 3 National-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.
  • 4 National-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. Electronic address: limin65@mail.sysu.edu.cn.
  • 5 Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China. Electronic address: shenchuangpeng@gzucm.edu.cn.
  • 6 Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou 510801, China. Electronic address: huangheq1125@163.com.
PMID: 38885580 DOI: 10.1016/j.phymed.2024.155780
Abstract

Background: The suppression of the Fibroblast Growth Factor 21/Fibroblast Growth Factor receptor 1 (FGF21/FGFR1) signaling pathway is considered as a vital factor in the type 2 diabetes mellitus (T2DM) progression. Our previous study showed that gentiopicroside (GPS), the main active compound present in Gentiana macrophylla Pall., has the capacity to control disorders related to glucose and lipid metabolism in individuals with T2DM. Nevertheless, the specific mechanism remains unclear.

Purpose: In light of the fact that the PharmMapper database suggests FGFR1 as the target of GPS, our investigation aims to determine if GPS can enhance glucose and lipid metabolism issues in T2DM by modulating the FGF21/FGFR1 signaling pathway.

Methods: In this study, we used palmitic acid (PA)-induced HepG2 cells and db/db mice to investigate the function and mechanism of GPS in the FGF21/FGFR1 signaling pathway. To examine the interaction between GPS and FGFR1, researchers performed Cellular Thermal Shift Assay (CETSA) and Surface Plasmon Resonance (SPR) analysis.

Results: The results suggest that GPS activates the traditional metabolic pathways, including PI3K/Akt and AMPK, which are the subsequent stages of the FGF21/FGFR1 pathway. This activation leads to the enhancement of glucose and lipid metabolism issues in PA-treated HepG2 cells and db/db mice. Furthermore, the depletion of FGFR1 has been noticed to oppose the stimulation of PI3K/Akt and AMPK pathways by GPS in HepG2 cells subjected to PA. Notability, our research affirms that GPS binds directly to FGFR1, hindering the ubiquitinated degradation of FGFR1 by neural precursor cells expressing developmentally decreased protein 4 (NEDD4) and ultimately promoting FGF21 signal transduction.

Conclusion: This study demonstrates that GPS targeting FGFR1 activates the PI3K/Akt and AMPK pathways, which is an important mechanism for its treatment of T2DM.

Keywords

FGF21/FGFR1 pathway; Gentiopicroside; Type 2 diabetes mellitus.

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