Gentiopicroside improves NASH and liver fibrosis by suppressing TLR4 and NLRP3 signaling pathways - 23/07/24
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Gentiopicroside (GPS) can ameliorate NASH and inhibit fibrogenesis, with potential mechanisms involving the regulation of TLR4 and NLRP3 signaling pathways. |
• | Targeting the suppression of macrophage-mediated inflammatory responses with GPS is a promising strategy for treating NASH and fibrosis by ameliorating hepatocyte pyroptosis and HSC activation. |
• | We have shown for the first time that GPS regulates the TLR4 signaling pathway. |
Abbreviations : ALT, AST, ATP, BMDM, Bmp7, Caspase1, CCCP, Collagen Ⅰ, DAPI, ELISA, FBS, GPS, GS, GSDMD, H&E, HCC, HFD, HFHC, HSC, IL, LPS, M1, M2, MCD, MCP-1/Ccl2, M-CSF, MDM, Mmp13, MYD88, NAFLD, NAS, NASH, NF-κB, NLRP3, OA, PA, PBS, PFA, QRT-PCR, Spp1, TC, TG, TGF-β, Timp1, TLR4, TNF-α, WB, α-SMA
Keywords : Non-alcoholic steatohepatitis, Fibrosis, Gentiopicroside, Macrophages, NLRP3, TLR4
Plan
Vol 177
Article 116952- août 2024 Retour au numéro
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