Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, Palbociclib cost decreased phosphorylation of JNK and c-jun, lower mitochondrial H2O2 levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction

of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation. (HEPATOLOGY 2012;56:281–290) Peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily, controls the expression of a battery of genes involved in lipid homeostasis including those encoding peroxisomal and mitochondrial enzymes that carry out fatty acid catabolism. PPARα is mainly expressed in organs that are critical in fatty acid catabolism, such as liver, heart, and kidney.1-3 Perhaps the most critical role of PPARα is to modulate hepatic fatty acid catabolism. In untreated mice, PPARα controls constitutive expression of NVP-AUY922 cost mitochondrial

fatty acid β-oxidation enzymes.4 During periods of starvation in mice Montelukast Sodium PPARα is activated, resulting in induction of both mitochondrial and peroxisomal fatty acid catabolism.5 Notably, in the course of spontaneous and ligand-induced activation of fatty acid catabolism excess H2O2 is produced as a byproduct of induction of peroxisomal acyl-CoA oxidase. Reactive oxygen species (ROS) are also produced during mitochondrial fatty acid β-oxidation. Although this increase in H2O2 is dealt with in part by catalase, glutathione peroxidase, and manganese superoxide dismutase, the cellular responses to ROS are saturated upon the massive activation of fatty

acid catabolism that occurs after ligand activation of PPARα. Consequently, increased PPARα activity during accelerated fatty acid catabolism is associated with increased expression of free-radical scavengers such as catalase and Cu/Zn dismutase6 and mitochondrial uncoupling proteins (UCPs) that may serve to reduce mitochondrial ROS levels.7, 8 Both direct and indirect effects suggest that PPARα may serve a protective role to combat the deleterious side effects of fatty acid catabolism, thus preserving, in particular, mitochondrial function. Increased ROS levels are frequently associated with hepatotoxicity produced by overdose of drugs such as acetaminophen (APAP). APAP, the most common nonprescription analgesic used for pain relief and antipyresis, is a representative compound that causes liver toxicity upon overdose and is a significant public health concern due to occasional overdose in children and adults.