ROS homeostasis, a key determinant in liver ischemic-preconditioning

Abstract

Reactive Oxygen Species (ROS) are key mediators of ischemia-reperfusion injury but also required for the induction of the stress response that limits tissue injury and underlies the protection provided by ischemic-preconditioning protocols. Liver steatosis is an important risk factor for liver transplant failure. Liver steatosis is associated with mitochondrial dysfunction and excessive mitochondrial ROS production. Studies aiming at decreasing the sensibility of the steatotic liver to ischemia-reperfusion injury using pre-conditioning protocols, have shown that the steatotic liver has a reduced capacity to respond to these protocols. Recent studies indicate that these effects are related to a reduced capacity of the steatotic liver to respond to elevated ROS levels following reperfusion by inducing a compensatory response. This failure to respond to ROS is associated with reduced levels of antioxidants, mitochondrial damage, hepatocyte cell death, activation of the immune system and induction of pro-fibrotic mediators.

Graphical abstract

Response to IR in normal vs steatotic liver. Induction of antioxidant systems in the normal liver facilitates survival in response to preconditioning protocols. Reduced PGC-1α activity in the steatotic liver limits antioxidant induction and results in extensive hepatocyte cell death. IR, Ischemia-Reperfusion; IPC, Ischemic Preconditioning; and ROS, Reactive Oxygen Species.