Gentiopicroside improves NASH and liver fibrosis by suppressing TLR4 and NLRP3 signaling pathways

  • Biomed Pharmacother. 2024 Aug:177:116952. doi: 10.1016/j.biopha.2024.116952.
Qiuhong Yong  1 ,  Chaoyuan Huang  2 ,  Bonan Chen  3 ,  Jinqi An  1 ,  Yiyuan Zheng  4 ,  Lina Zhao  5 ,  Chong Peng  6 ,  Fengbin Liu  7
Affiliations
  • 1. The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China; Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 2. The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 3. Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 4. Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 5. Department of Hepatobiliary of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou, China.
  • 6. Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Hepatobiliary of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou, China.
  • 7. Baiyun Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Lingnan Institute of Spleen and Stomach Diseases, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address: [email protected].
PMID: 38917754 DOI: 10.1016/j.biopha.2024.116952
Abstract

Background: Non-alcoholic steatohepatitis (NASH) and liver fibrosis are progressive conditions associated with non-alcoholic fatty liver disease (NAFLD), characterized by hepatocyte Pyroptosis and hepatic stellate cell (HSC) activation. Gentiopicroside (GPS) has emerged as a potential treatment for NASH, yet its underlying mechanism remains unclear.

Aim: To confirm that GPS can improve NASH and liver fibrosis by blocking the NLRP3 signaling pathway STUDY DESIGN: Initially, different animal models were used to study the effects and mechanisms of GPS on NASH and fibrosis. Subsequent in vitro experiments utilized co-cultures and Other techniques to delve deeper into its mechanism, followed by validation of the findings in mouse liver tissues.

Methods: C57BL/6 mice were fed high-fat, high-cholesterol (HFHC), or methionine-choline-deficient (MCD) diets to induce NASH and fibrosis. RAW264.7 cells and born marrow bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP to induce inflammation, then co-cultured with primary hepatocytes and HSCs, treated with GPS, and its efficacy and mechanism were analyzed.

Results: In vivo, GPS alleviated NASH and liver fibrosis by inhibiting the NLRP3 pathway. In vitro, GPS attenuated inflammation induced by BMDMs by inhibiting TLR4 and NLRP3 signaling pathways, and Co-culture studies suggested that GPS reduced hepatocyte Pyroptosis and HSC activation, which was also confirmed in liver tissues CONCLUSION: GPS improves NASH and liver fibrosis by inhibiting the TLR4 and NLRP3 signaling pathways. The specific mechanism may be related to the suppression of macrophage-mediated inflammatory responses, thereby reducing hepatocyte Pyroptosis and HSC activation.

Keywords
Fibrosis; Gentiopicroside; Macrophages; NLRP3; Non-alcoholic steatohepatitis; TLR4.
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