The nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPAR␣ in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPAR␣-null mice. Primary hepatocytes from wild-type but not PPAR␣-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPAR␣-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPAR␣, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPAR␣-null mice. Of the 815 genes regulated by WY in wild-type mice (p < 0.001; >1.5-fold or <؊1.5-fold), only two genes were regulated similarly by WY in PPAR␣-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPAR␣ controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

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