Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3β activity in mouse partial hepatectomy

Xueya Yao; Yingxiang Liu; Yongheng Sui; Miao Zheng; Ling Zhu; Quanfu Li; Michael Garnet Irwin; Liqun Yang; Qionghui Zhan; Jie Xiao

Biomedicine & Pharmacotherapy (Aug 2024)

Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3β activity in mouse partial hepatectomy

Xueya Yao,
Yingxiang Liu,
Yongheng Sui,
Miao Zheng,
Ling Zhu,
Quanfu Li,
Michael Garnet Irwin,
Liqun Yang,
Qionghui Zhan,
Jie Xiao

Affiliations

Xueya Yao: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
Yingxiang Liu: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
Yongheng Sui: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
Miao Zheng: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
Ling Zhu: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
Quanfu Li: Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
Michael Garnet Irwin: Department of Anaesthesiology, University of Hong Kong, China
Liqun Yang: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China; Corresponding authors at: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China.
Qionghui Zhan: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China; Corresponding authors at: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China.
Jie Xiao: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China; Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China; Corresponding authors at: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China.

Journal volume & issue: Vol. 177
p. 117038

Abstract

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Introduction: 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. Objectives: 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. Conclusion: 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.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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