PPAR alpha-dependent induction of liver microsomal esterification of estradiol and testosterone by a prototypical peroxisome proliferator

Fatty acyl-coenzyme A:estradiol acyltransferase in liver microsomes catalyz es the formation of estradiol fatty acid esters. These estrogen esters are extremely lipophilic and have prolonged hormonal activity because they are slowly metabolized and slowly release estradiol. Our previous studies showe d that treatment of female rats with clofibrate or gemfibrozil (peroxisome proliferators commonly used as hypolipidemic drugs) markedly stimulated the liver microsomal esterification of estradiol. Although clofibrate administ ration is a potent inducer of liver microsomal fatty acyl-coenzyme A.-estra diol acyltransferase in rats, it is a poor inducer in mice. In contrast to these observations, Wy-14,643 (an exceptionally potent prototypical peroxis ome proliferator) is a strong inducer of fatty acyl-coenzyme A:estradiol ac yltransferase in mice. To explore the role of PPAR alpha in the induction o f fatty acyl-coenzyme A:estradiol acyltransferase and fatty acyl-coenzyme A :testosterone acyltransferase activities by peroxisome proliferators, we fe d 0.1% Wy-14,643 to female wild-type and PPARa null mice for 11 d. The live r microsomal acyl-coenzyme A:estradiol acyltransferase and acyl-coenzyme A: testosterone acyltransferase activities were increased 4- to 5-fold in wild -type mice fed Wy-14,643, but no increase was observed in null mice. These results demonstrate that induction of acyl-coenzyme A:estradiol acyltransfe rase and acyl-coenzyme A:testosterone acyltransferase activities by a proto typical peroxisome proliferator is dependent on PPAR alpha.