In this study is presented the effect of fenofibrate, a prototypical peroxisome proliferator of the fibrate class, on wild-type and peroxisome proliferator-activated receptor alpha (PPARalpha)-/- mouse liver FA profile, desaturase mRNA levels, and activities. We established that, following peroxisome proliferator exposure, the hepatic FA profile was greatly modified. These modifications in hepatic FA content required the expression of PPARalpha, as they are suppressed in transgenic mice deficient in this nuclear receptor. Following peroxisome proliferator exposure, delta6- and delta5-desaturase mRNA levels and activities were increased in wild-type but not in PPARalpha-deficient mouse liver. These results suggest the involvement of PPARalpha in the control of hepatic delta6- and delta5-desaturases in mice. Their roles in minimizing long-chain PUFA depletion in the liver during peroxisome proliferator exposure are discussed.