PGC-1α downregulation in the steatotic liver enhances ischemia-reperfusion injury and impairs ischemic preconditioning

Abstract

Liver steatosis is associated with mitochondrial dysfunction, elevated ROS levels and a enhanced sensitivity of ischemia-reperfusion (IR) injury and a very limited response to preconditioning protocols. In this study we aimed to determine if the downregulation in the steatotic liver of peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α), a master regulator of mitochondrial metabolism and reactive oxygen species (ROS), that is known to play a relevant role in liver metabolic control, could be responsible for the sensitivity of the steatotic liver to ischemic damage.We found that PGC-1α is induced in the normal liver, following an IR protocol and this induction correlates with increased levels of antioxidant proteins. This induction is severely curtailed in the steatotic liver, and results in a limited induction of antioxidant proteins. PGC-1α-/- mice under chow diet do not have steatotic livers, but show an enhanced sensitivity to IR injury and a lack of response to ischemic preconditioning, that recapitulates the behaviour of the steatotic liver in terms of liver damage, although the inflammatory response differers between both models. We used an in vitro model to analyze how PGC-1α expression is regulated by changing O2 tensions, and found that hypoxia (1% O2) downregulates PGC-1α while reoxygenation (3% O2) induces it, and is responsible for the recovery of antioxidant gene expression following the ischemic period. [Conclusion]: PGC-1α plays an important role in the protection against IR injury in the liver that is likely associated with its capacity to induce antioxidant gene expression.