Antcin A alleviates pyroptosis and inflammatory response in Kupffercells of non-alcoholic fatty liver disease by targeting NLRP3

• Published in: International immunopharmacology 2021-11, Vol.100, p.108126-108126, Article 108126
• Main Authors: Ruan, Shuiliang, Han, Chenyang, Sheng, Yongjia, Wang, Jin, Zhou, Xiaohong, Guan, Qiaobing, Li, Wenyan, Zhang, Caiqun, Yang, Yi
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Alzheimer's disease; Animals; Antcin A; Antioxidants; Binding; Box beams; Caspase 1 - metabolism; Catalase; Cell Survival; Cells, Cultured; Chemical compounds; Computational neuroscience; Cortex (frontal); Cytokines; Diet, High-Fat; Disease Models, Animal; Fatty liver; Free radicals; Glutathione; Glutathione transferase; IL-1β; In vivo methods and tests; Inflammasomes - metabolism; Inflammation; Inflammatory response; Interleukin 6; Interleukin-1beta - metabolism; Kupffer cells; Kupffer Cells - metabolism; Lipopolysaccharides; Liver - pathology; Liver diseases; Long term memory; Memory tasks; Mice; Mice, Inbred C57BL; Molecular docking; mRNA; Neurodegenerative diseases; Neurological diseases; Neuroprotection; NF-κB protein; Nigericin; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Non-alcoholic fatty liver disease; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Object recognition; Oxidative stress; Pattern recognition; Pharmacology; Polymerase chain reaction; Pyroptosis; Pyroptosis - drug effects; Spatial analysis; Spatial discrimination learning; Spatial memory; Steroids - pharmacology; Tumor necrosis factor-α
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.108126

[Display omitted] •Antcin A can inhibit the activation of KCs after targeting NLRP3, so as to inhibit inflammatory response and protect the liver.•As a new triterpene compound, Antcin A has great development potential, especially for the treatment of liver injury. Pyroptosis, a pattern of inflammatory death, is regulated by NLRP3-Caspase-1 inflammasome and GSDMD-FL protein. Antcin A is a small triterpenoid molecule. In this study, Kupffer cells (KC) were used for in vitro model, which were treated with LPS and Nigericin (L/N) to induce pyroptosis. ELISA was used to determine the influence of Antcin A on the expression of inflammatory factors, IF was utilized to investigate NLRP3 and Caspase-1, PI staining was used to detect the opening level of membrane pores in KCs, C57BL/6J wild-type mice were fed with high-fat diet to construct a NAFLD model, and were simultaneously treated with Antcin A. H&E staining was used to detect hepatic pathological changes in mice, oil red staining was utilized to detect hepatic fat deposits in mice, IHC was used to detect the expression of NLRP3 and Caspase-1, Western blot was used to detect the expression levels of NLRP3 inflammasome (including NLRP3, ASC, Caspase-1, GSDMD-FL and GSDMD-NT). Pull-down assay and immunoprecipitation assay were used to detect the binding between Antcin A and NLRP3. As a result, Antcin A could significantly inhibit the occurrence of pyrolysis, decrease the expression of inflammatory factors, inhibit the activation and assembly of NLRP3 inflammasome, and significantly down-regulate the expression of NLRP3, Caspase-1 and GSDMD-NT in KCs. In NAFLD mice, Antcin A could suppress the inflammatory response in liver tissues of mice, reduce lipid deposition, down-regulate the levels of ALT and AST, and improve liver function in mice. Antcin A could also inhibit the activation of NLRP3 inflammasome in liver tissue and decrease the level of inflammatory factors. In the study of mechanism, we revealed that Antcin A could inhibit the assembly and activation of NLRP3 inflammasome by binding with NLRP3. In summary, in this study, we found that Antcin A could inhibit pyroptosis in KC and alleviate the inflammatory response of liver tissue in NAFLD by targeting NLRP3 inflammasome, which was one of the mechanisms of Anctin A in protecting liver.