Activation of AMPK by Metformin Attenuates Marginal Graft Injury via Promoting Mitochondrial Biogenesis

Abstract

Background: AMP-activatedprotein kinase (AMPK) could sense ATP depletion and promote mitochondrialrespiratory function. The role of AMPK in marginal graft injury after livingdonor liver transplantation (LDLT) was still unclear. In this study, we aimedto investigate the therapeutic value of AMPK activator - metformin in treatingmarginal graft injury and to explore the underlying mechanism. Methods: Correlationof AMPK and liver graft injury as well as mitochondrial function was analyzed bothin clinical LDLT and rat orthotopic liver transplantation model usingsmall-for-size fatty graft. The role of AMPK in mediating marginal graft injurywas explored by AMPK knock in (AMPK+/-) mice models and in vitro AMPKinhibition study. The therapeutic value of AMPK activator - metformin was investigatedin mice model underwent partial ischemia/reperfusion plus major hepatectomy. Themitochondrial membrane potential alteration was also studied by intravitalconfocal imaging in animal models. Results: Lowerratio of phosphorylated AMPK was found in small-for-size fatty graft associatedwith delayed recovery of graft function in both clinical series (POD7 TBil: 156vs 70mg/dL, p< 0.01) and animalmodels. Also, mitochondrial dysfunction indicated by depolarization of membranepotential and ATP depletion were more severe in small-for-size fatty graftcompared to normal graft (total ATP: 12.0 vs 35.5nmol/g, p< 0.01). Overexpressionof AMPK and metformin treatment ameliorated liver injury (ALT: 212 vs 329IU/L,AST: 130 vs 184IU/L, p< 0.01) andrestored mitochondrial membrane polarization in mice model (Figure 1). Specifically,mitochondrial biogenesis mediated by PGC-1a nuclear translocation was increasedin both AMPK overexpression and metformin treatment mice models (Figure 2), butwas diminished when AMPK inhibited in vitro. Conclusion: Activationof AMPK by metformin could attenuate I/R injury via promoting mitochondrialbiogenesis, which might have therapeutic value for marginal graft injury duringLDLT.