Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside F2 Restrains Hepatic Steatosis and Inflammation by Altering the Binding Affinity of Liver X Receptor Coregulators

  • Kyurae Kim (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST) ;
  • Myung-Ho Kim ( Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST) ;
  • Ji In Kang (Biomedical Science and Engineering Interdisciplinary Program, KAIST) ;
  • Jong-In Baek (Department of Biological Sciences, KAIST) ;
  • Byeong-Min Jeon (Department of Biological Sciences, KAIST) ;
  • Ho Min Kim (Biomedical Science and Engineering Interdisciplinary Program, KAIST) ;
  • Sun-Chang Kim (Department of Biological Sciences, KAIST) ;
  • Won-Il Jeong (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST)
  • Received : 2023.08.02
  • Accepted : 2023.10.19
  • Published : 2024.01.01
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Abstract

Background: Ginsenoside F2 (GF2), the protopanaxadiol-type constituent in Panax ginseng, has been reported to attenuate metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanism of action is not fully understood. Here, this study investigates the molecular mechanism by which GF2 regulates MASLD progression through liver X receptor (LXR). Methods: To demonstrate the effect of GF2 on LXR activity, computational modeling of protein-ligand binding, Time-resolved fluorescence resonance energy transfer (TR-FRET) assay for LXR cofactor recruitment, and luciferase reporter assay were performed. LXR agonist T0901317 was used for LXR activation in hepatocytes and macrophages. MASLD was induced by high-fat diet (HFD) feeding with or without GF2 administration in WT and LXRα-/- mice. Results: Computational modeling showed that GF2 had a high affinity with LXRα. LXRE-luciferase reporter assay with amino acid substitution at the predicted ligand binding site revealed that the S264 residue of LXRα was the crucial interaction site of GF2. TR-FRET assay demonstrated that GF2 suppressed LXRα activity by favoring the binding of corepressors to LXRα while inhibiting the accessibility of coactivators. In vitro, GF2 treatments reduced T0901317-induced fat accumulation and pro-inflammatory cytokine expression in hepatocytes and macrophages, respectively. Consistently, GF2 administration ameliorated hepatic steatohepatitis and improved glucose or insulin tolerance in WT but not in LXRα-/- mice. Conclusion: GF2 alters the binding affinities of LXRα coregulators, thereby interrupting hepatic steatosis and inflammation in macrophages. Therefore, we propose that GF2 might be a potential therapeutic agent for the intervention in patients with MASLD.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT, (2021R1A2C3004589, RS-2023-00223831, 2022M3A9B6017654), and the Ministry of Education (2022R1A6A3A13071493), Korean government, South Korea.

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