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

Abstract

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 of 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 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 (hazard ratio 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 downregulated 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.

Current status of glucocorticoid usage in solid organ transplantation

“…Activation of AMPK increased the phosphorylation of GR at serine-211 and reversed GC-induced hepatic steatosis and suppressed GC-mediated stimulation of glucose production in rats[ 143 ]. Interestingly, impaired AMPK activity was associated with steatotic graft injury in patients with living donor liver transplantation[ 144 ]. Thus, whether AMPK activators can ameliorate the metabolic side effects of GCs in SOT warrants investigation.…”

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation

“…Mesenchymal stem cells (MSCs) ameliorated hepatocellular apoptosis mediated by PINK1-dependent mitophagy in hepatic IRI through adenosine monophosphate-activated protein kinase (AMPK)α activation [ 28 ]. This study was echoed by our recent finding, which reported that a compromised AMPK–PGC1α axis exacerbated steatotic graft injury by dysregulating mitochondrial homeostasis through impairment of biogenesis [ 29 ].…”

“…Increased macrovesicular steatosis (>30%) was associated with increased histological damage, hepatic function derangement and reduced survival after liver transplantation according the systemic review [ 43 ]. Moreover, our recent study demonstrated that graft steatosis over 10% was an independent risk factor for poor post-transplant survival and was associated with acute graft injury after living donor liver transplantation (LDLT) [ 29 ]. Along with the mechanism underlying NAFLD being clarified, the mechanisms of severe IRI in steatotic grafts are paid more attention [ 44 ].…”

Current Status of Glucocorticoid Usage in Solid Organ Transplantation

“…Activation of AMPK increased the phosphorylation of GR at Serine-211 and reversed GC-induced hepatic steatosis and suppressed GCmediated stimulation of glucose production in rats [143] . Interestingly, impaired AMPK activity was associated with steatotic graft injury in patients with living donor liver transplantation [144] . Thus, whether AMPK activators can ameliorate the metabolic side effects of GCs in SOT warrants investigation.…”