Background. The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in NASH progression as mitochondria are the main cellular site of fatty acids oxidation, ATP synthesis and reactive oxygen species (ROS) production.
Aims. 1) to evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH patients and ratmodel; 2) To assess the acute liver damage induced by ischemia reperfusion in rats with NASH.
Methods. Mitochondria were extracted from human and liver NASH model. Proton leak, H2O2 synthesis, GSH/GSSG, HNE protein adducts, UCP2 expression and ATP homeostasis were evaluated before and after ischemia/reperfusion injury.
Results. NASH mitochondria exhibit an increased rate of proton leak due to hepatocytes UCP2 expression. These results correlated with increased mitochondrial hydrogen peroxide production and UCP2-HNE- adducts, and decreased hepatic ATP content that is not dependent on mitochondrial ATPase dysfunction. The application of an ischemia/reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibit UCP2 over-expression and mitochondrial oxidative stress.
Conclusions. During NASH development UCP2 upregulation induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischemia/reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.