Soyasaponin Ⅱ Ameliorates Acute Liver Failure In Mice By Diminishing Y-box-binding Protein 1 Phosphorylation And Suppressing NLRP3-inflammasome Priming In Macrophages

BackgroundsAcute liver failure(ALF)is an end-stage complication of sudden hepatocyte injury and rapid development of liver dysfunction caused by virus infection,drug toxicity,liver ischemia,autoimmune hepatitis and so on.More and more evidence has showed that the sayasaponins in legumes have potential anti-inflammatory and antioxidant activities,but whether soyasaponins Ⅱ(SS Ⅱ)play a preotective role in acute liver failure has remain elusive.ObjectivesHere,we aimed to explore whether SS Ⅱ has a potential therapeutic effect in acute liver failure,and investigate its potential molecular targets and signal pathway regulation mechanism by using multigroup techniques,so as to provide new strategies for clinical diagnosis and treatmentMethodsIn this study,the mouse model of acute liver failure was established by intraperitoneal injection of lipopolysaccharide(LPS)/D-galactosamine(D-GalN),the level of SS Ⅱ in cecum and liver was detected by high performance liquid chromatography-mass spectrometry(HPLC-MS),and the transcription regulatory molecules and signal pathways of SS Ⅱ on hepatic macrophages were detected by RNA sequencing analysis.The potential molecular targets of SS Ⅱ on hepatic macrophages were screened by proteomics,and the detailed molecular biological mechanism of downstream transcription was verified by luciferase reporter gene system and chromatin immunoprecipitation sequencing(CHIP-seq).ResultsThe pathological state of acute liver failure induced by LPS/D-GalN significantly decreased the level of SSⅡ in cecum and liver of mice,and SSⅡ pretreatment for three days could effectively improve the symptoms of liver injury and reduce the level of inflammatory factor interleukin-1β(IL-1β)in peripheral blood.Based on transcriptome and proteomic sequencing analysis,it was confirmed that SSⅡ inhibited the phosphorylation and nuclear translocation of Y-Box binding protein 1(YB-1)in hepatic macrophages and prevented the phosphorylation of YB-1 protein into the nucleus.These procedures prevent YB-1 bound to the Nlrp3 mRNA promoter region that dimished the NLRP3 inflammasome priming as well as the production of IL-1β during liver failure and improved the inflammatory response induced by LPS/D-GalN.Finally,the liver tissue sections of the control group and patients with acute liver failure were included,and the level of p-YB-1 in CD64-labeled macrophages in the liver of ALF patients was higher than that of the control group.ConclusionsOur data shows that soyasaponin Ⅱ which serves as a novel inhibitor for YB-1 phosphorylation and Nlrp3 inflammasome priming could protect mice against LPS/GalN induced acute liver failure.