Mitochondrial changes in hepatic steatosis: The effect of ischemia-reperfusion injury and ischemic preconditioning

Abstract

Background: Hepatic steatosis is associated with poor post-operative outcome after liver surgery. It was hypothesised that steatotic livers are susceptible to ischemia-reperfusion injury (IRI) and one proposed mechanism is mitochondrial dysfunction. Mitochondria produce the bulk of cellular energy and impaired mitochondrial function (MF) leads to cellular death. Ischemic preconditioning (IPC) is thought to decrease liver injury and improve hepatic MF. However, the relationship between hepatic steatosis and MF in the setting of IPC and IRI is poorly understood. Aim: Investigate the impact of hepatic steatosis on liver MF subjected to cold ischemia and warm IRI in the presence or absence of IPC. Methods: Systematic reviews were undertaken to evaluate three key issues: 1) Relationship between hepatic steatosis and outcome in liver surgery, 2) Effect of hepatic steatosis on hepatic MF after IRI, and 3) Effect of IPC on outcome in liver surgery. Experimental studies was conducted in appropriate mouse and rat models of hepatic steatosis, investigating the impact of hepatic steatosis on liver MF subjected to prolonged cold ischemia or warm IRI. The effect of IPC on hepatic MF was also evaluated. Findings: Reviews indicated that hepatic steatosis associates with poor outcome after liver surgery and impaired cellular bioenergetics was a factor. Additionally, IPC decreased conventional liver injury markers but did not improve clinical outcome. I demonstrated that steatotic animal livers developed MF impairment, particularly Complex I (CI). Steatotic livers acquire additional MF impairment after cold ischemia, occurring faster in livers with >30% steatosis. After warm IRI, steatotic livers developed decreased CI function. IPC improved CI efficiency in livers with <30% steatosis subjected to cold ischemia but did not influence MF in livers with >30% steatosis subjected to cold ischemia or warm IRI. Conclusions: The results demonstrated that hepatic steatosis is associated with impaired MF, which worsened after IRI and contributed to the decreased tolerance of steatotic livers to IRI. IPC was effective on steatotic liver MF in certain settings. Future research should identify the underlying mechanism of impaired steatotic liver MF especially in clinical studies to develop mitochondrial-specific therapies, in order to improve outcome in patients with hepatic steatosis.