PPARα-Dependent Induction of Liver Microsomal Esterification of Estradiol and Testosterone by a Prototypical Peroxisome Proliferator

Abstract

Fatty acyl-coenzyme A:estradiol acyltransferase in liver microsomes catalyzes 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 showed 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 administration is a potent inducer of liver microsomal fatty acyl-coenzyme A:estradiol acyltransferase in rats, it is a poor inducer in mice. In contrast to these observations, Wy-14,643 (an exceptionally potent prototypical peroxisome proliferator) is a strong inducer of fatty acyl-coenzyme A:estradiol acyltransferase in mice. To explore the role of PPARalpha in the induction of fatty acyl-coenzyme A:estradiol acyltransferase and fatty acyl-coenzyme A:testosterone acyltransferase activities by peroxisome proliferators, we fed 0.1% Wy-14,643 to female wild-type and PPARalpha null mice for 11 d. The liver 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 acyltransferase and acyl-coenzyme A:testosterone acyltransferase activities by a prototypical peroxisome proliferator is dependent on PPARalpha.

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

“…In patients referred to a clinic for primary hyperlipidemia, an increased risk of ED was also observed in patients treated with fibrates [300]. Fibrates interact with PPARs [301], which in the liver stimulates microsomal esterification of estradiol and testosterone [302]. That may explain the increased prevalence of ED reported in patients treated with fibrates.…”

Fatty acid esters of steroids: Synthesis and metabolism in lipoproteins and adipose tissue

“…Fatty acylation of estradiol, testosterone, dehydroepiandrosterone, pregnenolone and corticosterone in rat liver was stimulated by 14-22-fold by oral clofibrate [13]. In PPAR␣ null (−/−) mice, however, a potent PPAR␣ agonist Wy-14,643 did not increase fatty acylation of estradiol or testosterone, suggesting that PPAR␣ was involved in the stimulatory effect of clofibrate on steroid esterification [22]. Accordingly, clofibrate did not increase the esterification of estradiol in tissues with less PPAR␣ expression compared to liver, such as in adipose tissue, uterus or brain [13].…”

Erectile Dysfunction

“…In patients referred to a clinic for primary hyperlipidemia, an increased risk of ED was also observed in patients treated with fibrates [232]. Fibrates interact with PPARs [233], which in the liver stimulates microsomal esterification of estradiol and testosterone [234]. That may explain the increased prevalence of ED reported in patients treated with fibrates.…”