Compromised AMPK-PGC1α Axis Exacerbated Steatotic Graft Injury by Dysregulating Mitochondrial Homeostasis in Living Donor Liver Transplantation

OBJECTIVE To investigate the association of graft steatosis with long-term outcome, and to elucidate the mechanism of steatotic graft injury in adult living donor liver transplantation. SUMMARY BACKGROUND DATA The utilization of steatotic graft expands the donor pool for living donor liver transplantation (LDLT). However, it remains controversial due to its high morbidity and mortality. Elucidating the mechanism of steatotic graft injury is crucial to develop therapeutic strategies targeting at graft injury and to further expand the donor pool. METHODS Five hundred and thirty patients receiving LDLT were prospectively included for risk factor analysis and outcome comparison. Rat orthotopic liver transplantation, in vitro functional experiments and mouse hepatic ischemia/reperfusion models were established to explore the mechanisms of steatotic graft injury. RESULTS We identified that graft with > 10% steatosis was an independent risk factor for long-term graft loss after LDLT (HR 2.652, p = 0.001), and was associated with shorter cancer recurrence-free survival and acute phase liver injury. Steatotic graft displayed distinct mitochondrial dysfunction, including membrane, calcium and energy homeostasis dysregulation. Specifically, the mitochondrial biogenesis was remarkably down-regulated in steatotic graft. Inhibition of AMPK-PGC1α axis impaired mitochondrial biogenesis and was lethal to fatty hepatocyte in vitro, whereas reactivation of AMPK promoted PGC1α-mediated mitochondrial biogenesis and attenuated liver injury via restoring mitochondrial function in animal model. CONCLUSIONS We provided a new mechanism that compromised AMPK-PGC1α axis exacerbated steatotic graft injury in LDLT by dysregulating mitochondrial homeostasis through impairment of biogenesis.