%0 Journal Article %T Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3β activity in mouse partial hepatectomy. %A Yao X %A Liu Y %A Sui Y %A Zheng M %A Zhu L %A Li Q %A Irwin MG %A Yang L %A Zhan Q %A Xiao J %J Biomed Pharmacother %V 177 %N 0 %D 2024 Aug 12 %M 39002441 %F 7.419 %R 10.1016/j.biopha.2024.117038 %X BACKGROUND: Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is widely used for sedation and anesthesia in patients undergoing hepatectomy. However, the effect of DEX on autophagic flux and liver regeneration remains unclear.
OBJECTIVE: This study aimed to determine the role of DEX in hepatocyte autophagic flux and liver regeneration after PHx.
METHODS: In mice, DEX was intraperitoneally injected 5 min before and 6 h after PHx. In vitro, DEX was co-incubated with culture medium for 24 h. Autophagic flux was detected by LC3-II and SQSTM1 expression levels in primary mouse hepatocytes and the proportion of red puncta in AML-12 cells transfected with FUGW-PK-hLC3 plasmid. Liver regeneration was assessed by cyclinD1 expression, Edu incorporation, H&E staining, ki67 immunostaining and liver/body ratios. Bafilomycin A1, si-GSK3β and Flag-tagged GSK3β, α2-ADR antagonist, GSK3β inhibitor, AKT inhibitor were used to identify the role of GSK3β in DEX-mediated autophagic flux and hepatocyte proliferation.
RESULTS: Pre- and post-operative DEX treatment promoted liver regeneration after PHx, showing 12 h earlier than in DEX-untreated mice, accompanied by facilitated autophagic flux, which was completely abolished by bafilomycin A1 or α2-ADR antagonist. The suppression of GSK3β activity by SB216763 and si-GSK3β enhanced the effect of DEX on autophagic flux and liver regeneration, which was abolished by AKT inhibitor.
CONCLUSIONS: Pre- and post-operative administration of DEX facilitates autophagic flux, leading to enhanced liver regeneration after partial hepatectomy through suppression of GSK3β activity in an α2-ADR-dependent manner.