Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3β activity in mouse partial hepatectomy - 23/07/24

Doi : 10.1016/j.biopha.2024.117038

Xueya Yao ^a,^b,^c,^{^{1
these authors contributed equally to this work.}} , Yingxiang Liu ^a,^b,^c,^{^{1
these authors contributed equally to this work.}} , Yongheng Sui ^a,^b,^c,^{^{1
these authors contributed equally to this work.}} , Miao Zheng ^a,^b,^c , Ling Zhu ^a,^b,^c , Quanfu Li ^d , Michael Garnet Irwin ^e , Liqun Yang ^a,^b,^c,^⁎,^{^{2
these authors contributed equally to this work.}} , Qionghui Zhan ^a,^b,^c,^⁎,^{^{2
these authors contributed equally to this work.}} , Jie Xiao ^a,^b,^c,^⁎,^{^{2
these authors contributed equally to this work.}}
^a Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
^b Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China
^c Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
^d Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
^e Department of Anaesthesiology, University of Hong Kong, China

^⁎Corresponding authors at: Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University, School of MedicineShanghaiChina

Abstract

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.

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Graphical Abstract

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Highlights

•	The pre- and post-operative use of DEX promotes liver regeneration after PHx.
•	DEX facilitates autophagic flux to support liver regeneration via α2-ADR.
•	GSK3β activity mediates DEX-induced autophagic flux facilitation.

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Abbreviations : DEX, α2-ADR, PHx, PMHs, FPKM, DEGs, GO, KEGG, BP, CC, MF, AML-12, BafA1, Atipa, SB, SC, ROIs, SEM, ANOVA, GSK3β, P-GSK3β, ADRs, CAMP

Keywords : Liver regeneration, Autophagic flux, Dexmedetomidine, Alpha2-adrenergic receptor, GSK3β

Plan

Introduction

Materials and methods

Animals and PHx model

Dexmedetomidine (DEX) treatment and reagent administration

Primary mouse hepatocytes (PMHs) isolation and cell line

RNA sequencing and analysis

Gene Ontology (GO) and Kyoto Encyclopedia of genes and genomes (KEGG) enrichment analysis

cDNA constructs

Pharmacological reagents and primary antibodies

Western blotting

Immunohistochemistry staining and H&E staining

Liver/body weight ratio

ALT, AST, IL-6 and TNF-α detection

ELISA

Flow cytometry and Edu test

Confocal fluorescence imaging

Statistical analysis

Results

Preoperative and postoperative administration of DEX promotes liver regeneration in mouse PHx model

DEX promotes liver regeneration by facilitating autophagic flux in hepatocytes

DEX enhances hepatocytic autophagic flux through α2-ADR

GSK3β activity affects the effect of DEX on autophagic flux and liver regeneration

Inhibition of GSK3β activity plays a key role in DEX-enhanced liver regeneration

Discussion

Conclusion

Funding

CRediT authorship contribution statement

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Article 117038- août 2024 Retour au numéro

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Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3β activity in mouse partial hepatectomy - 23/07/24

Abstract

Introduction

Objectives

Methods

Results

Conclusion

Graphical Abstract

Highlights

Plan

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