Dexmedetomidine Promotes Liver Regeneration By Activating AKT/GSK3beta/beta-catenin Pathway

Background and purposeLiver is characterized by its remarkable regenerative ability,but the ability could be damaged by huge injury,liver resection or liver transplantation.The liver can’t function as normal,resulting in poor prognosis and even liver failure.Liver regeneration is crucial for the prognosis of patients after hepatectomy.Dexmedetomidine(DEX)is widely used in perioperative management including anesthesia and intensive care.It has a protective effect on the liver,but its effect on liver regeneration is unknown.Therefore,the purpose of this study was to investigate the effect of DEX on liver regeneration.MethodThe study began with an in vivo experiment,70% hepatectomy(PHx)model was performed in mice with intraperitoneal injection of dexmedetomidine(25 μg/kg)30 min before surgery.Blood and liver samples were collected for further analysis at 48 h postoperatively(peak liver regeneration).And then in vitro experiments,mouse primary hepatocytes(MPH)were incubated with dexmedetomidine(10μm)for 24 h,and cell proliferation levels were measured from mRNA and protein levels,respectively.Next step is to explore the mechanics,transcriptome sequencing was performed on mouse liver tissue to explore the possible mechanisms,and then verified by western blot analysis.Finally,the effect of dexmedetomidine on liver regeneration was further confirmed using atipamezole by the blocking of the alpha2-adrenergic receptor.ResultsIn vivo experiment evidenced that dexmedetomidine significantly promoted liver regeneration in mice after 70% hepatectomy.After dexmedetomidine pretreatment,the ratio of residual liver weight to preoperative basal body weight was increased.Immunohistochemistry of Ki67,PCNA and Cyclin-D1 in liver tissues showed more proliferating liver cells after dexmedetomidine pretreatment.Compared with the control group,the mRNA and protein expression levels of cyclin and PCNA were increased.In vitro,dexmedetomidine promoted the proliferation of MPH.The expression levels of cyclin,PCNA mRNA and protein in MPH were increased after dexmedetomidine treatment.EdU and Ki67 immunofluorescence staining detected more proliferating MPH than the control.Transcriptome sequencing suggested that the AKT /GSK3beta/beta-catenin pathway may be the mechanism of the action of dexmedetomidine.In vivo and in vitro experiments,p-Akt,p-GSK3 beta and beta-catenin protein expression levels were increased after DEX treatment.Pretreatment with atipamezole reversed the proliferation effect of DEX on MPH and the effect of DEX on mouse liver regeneration.Both in vivo and in vitro,atipamezole pretreatment reduced the protein expression levels of p-Akt,p-GSK3 beta and beta-catenin.ConclusionOur study suggested that dexmedetomidine promotes liver regeneration through activation of AKT,inactivation of GSK3 beta and then accumulation of beta-catenin in cells,providing a potential adjunct for perioperative hepatectomy.