Stimulatory effect of peroxisome proliferators on estradiol esterification and its biological importance

Fatty acyl-CoA:estradiol acyltransferase that catalyzes the formation of estradiol fatty acid esters is present in liver and extrahepatic tissues of rats. Clofibrate and gemfibrozil (peroxisome proliferators that are commonly used hypolipidemic drugs) were potent inducers of rat liver microsomal acyl-CoA:estradiol acyltransferase (up to a 10-fold increase in the Vmax value over the controls). The Km value and the pH optimum for the liver microsomal esterification of estradiol were not appreciably altered by treatment of rats with clofibrate or gemfibrozil, suggesting an induction of the acyl-CoA:estradiol acyl-transferase normally present in untreated animals. This study is the first demonstration of an effect of an environmental agent on the esterification of estradiol. In contrast to the several-fold induction of acyl-CoA:estradiol acyltransferase in the liver of rats, clofibrate administration had little or no effect on estradiol acyltransferase in several extrahepatic tissues studied.; Studies with peroxisome proliferator-activated receptor alpha (PPARα) null mice and with wild-type control mice indicated that induction of hepatic acyl-CoA:estradiol acyltransferase by a prototypical peroxisome proliferator (Wy-14,643) was dependent on PPARα.; In studies with ovariectomized rats infused with estradiol, we observed that clofibrate administration had a selective stimulatory effect on the hormonal action of estradiol in the mammary glands but not in the uterus. These results suggested that estradiol fatty acid esters may be ‘mammary selective estrogens’, probably due to their high lipophilicity and the high lipid content of the mammary glands. Administration of clofibrate increased hepatic and fat esterase activity by about 2-fold, thereby, releasing more hormonally active free estradiol from fatty acid esters and providing a strong estrogenic stimulus to target tissues.; In an additional study, we determined the effect of clofibrate administration on the esterification of testosterone, pregnenolone, dehydroepiandrosterone and corticosterone by liver microsomes. Administration of clofibrate to rats stimulated the liver microsomal esterification of all of these steroids by more than 17-fold. The biological role of these steroid fatty acid esters is unknown.