The Role Of Hisone 3 Lysine 27 Trimethylation(H3K27me3)in The Pathogenesis Of Acute-on-chronic Liver Failure

Background and objective Acute-on-chronic liver failure(ACLF)is an acute deterioration of liver function followed with chronic liver diseases,accompanied with massive hepatocyte necrosis/apoptosis and recruitment of inflammatory cell,leading to fatal multi-system organ dysfunction with unacceptably high short-term mortality.Enhancer of zeste homolog 2(EZH2),one of the most important epigenetic regulators that contributes to silence of the target genes,is an indispensable histone methyltransferase catalyzing methyl groups to histone H3 at lysine 27(H3K27).Whether EZH2 and H3K27me3 involves in pathogensis of ACLF,particularly in regulating inflammatory cytokines during ACLF remains to be further explored.Methods Peripheral blood monocytes(PBMC)from ACLF patients,and liver tissues from lipopolysaccharide(LPS)/D-galactosamine(D-GalN)-induced acute liver failure mice were subj ected for EZH2 and H3K27 trimethylation(H3K27me3)using western blot.Intrahepeatic products of EZH2 and H3K27 were determined using immunohistochemistry.GSK126 pretreatments were carried out in LPS/D-GalN-induced acute liver failure mice,then survival analysis and pathology analysis were performed.Moreover,both sero and hpatic level pro-inflammatory cytokines were measured using enzyme-linked immunosorbent assay and real-time quantitive PCR(qPCR),respectively.GSK126 pretreatments were also carried out in PBMC upon LPS stimulation in vitro.The effects of GSK126 on pro-inflammatory cytokines were evaluated using qPCR.Results Compared to those in healthy controls,EZH2 and H3K27me3 in PBMC from ACLF showed significantly higher level.Similarly,LPS/D-GalN induced acute liver failure caused hepatic levels of EZH2 and H3K27me gradually increasing.Pathogologically,both EZH2 and H3K27me3 accumulated around focal areas of severe inflammation,along with inflammatory cell infiltration.Furthermore,pretreatment of GSK126 sighfinicatly attenuated liver injury and hepatic inflammation,with improving survivial.Additionally,GSK126 could limite tumor necrosis factor expression both in vivo and in vitro.Conclusion The current study suggested that EZH2 and H3K27me3 increased in both ACLF patients and LPS/D-GalN induced acute liver failure mice,and promoted pro-inflammatory cytokines in pathogensis of liver failure.It might provide a new explanation of ACLF pathogensis in epigenetic regulation,and EZH2/H3K27me3 might be a novel and potential target for ACLF therapy.