Mechanism for Control of HydroxymethylglutaryL Coenzyme A Reductase and Cytochrome P-450 Side Chain Cleavage Message and Enzyme in the Corpus Luteum*

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The present study was undertaken to investigate the mechanism for control of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase and cytochrome P-450 side chain cleavage (P-450scc), enzymes involved in the synthesis and processing of cholesterol in the corpus luteum of pregnant rats. The role of sterol and estradiol were investigated by administering 4-aminopyrazolo-[3,4d]pyrimidine (4-APP), aminoglutethimide and/or estradiol to day 12 hypophysectomized-hysterectomized pregnant rats. Estradiol treatment markedly increased mRNA levels of HMG-CoA reductase in the corpus luteum. This stimulatory effect of estradiol was specific for the reductase since the mRNA for luteal P-450scc did not increase following estradiol treatment. To determine whether estradiol's action on HMG-CoA reductase mRNA was mediated by changes in cellular free cholesterol, the separate and combined action of estradiol and either 4-APP or aminoglutethimide on both sterol content and HMG-CoA reductase expression was examined. The estradiol induced rise in HMG-CoA reductase was not accompanied by a decrease in luteal cholesterol. 4-APP treatment depleted cholesterol in the corpus luteum and induced a greater increase in HMG-CoA reductase mRNA than estradiol. Combined treatment with estradiol and 4-APP resulted in a synergistic increase in HMG-CoA reductase mRNA despite the fact that estradiol did not further reduce the 4-APP induced decrease in luteal sterol content. This indicates that luteal cells possess an estradiol-mediated mechanism for up-regulation of HMG-CoA reductase gene expression which is distinct from the cholesterol negative feedback regulation. However, estradiol stimulation of HMG-CoA reductase was totally inhibited when sterol content was elevated by aminoglutethimide, suggesting that estradiol stimulation of HMG-CoA reductase expression is not sufficient to overcome the negative regulatory effect of cholesterol. In contrast to HMG-CoA reductase mRNA which appears to be controlled by sterol and estradiol, P-450scc mRNA levels remained constant in corpora lutea despite wide changes in sterol and steroid content induced by either 4-APP, aminoglutethimide or estradiol treatment. However, interestingly, aminoglutethimide increased substantially the content of P-450scc protein. This increase in P-450scc enzyme was not due to a greater amount of translatable message since similar levels of immunoprecipitable 35S-P-450scc were translated in vitro from luteal mRNA of rats treated with or without aminoglutethimide. In summary, results of this investigation have revealed that the expression of HMG-CoA reductase and cytochrome P-450scc are controlled by totally different mechanisms in the rat corpus luteum.(ABSTRACT TRUNCATED AT 400 WORDS)