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Papers In Press, published online ahead of print November 4, 2002
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Submitted on August 16, 2002
Department of Medical Chemistry, Kochi Medical School, Nankoku 783-8505
Corresponding Author: todak{at}kochi-ms.ac.jp
Peroxisome proliferator-activated receptors (PPARs) play important roles in the metabolic regulation of lipids including steroids. In this study, we investigated whether fenofibrate, a ligand for PPARa, could influence estrogen synthesis in vivo in the ovary of mice. As reported, chronic treatment of C57BL6/J female mice with various amounts of fenofibrate as a diet reduced the serum triglycerides level and induced hepatomegaly in a dose-dependent manner. Northern blot analyses using hepatic RNA confirmed the induction of classical PPARa-target genes including acyl-CoA oxidase and lipoprotein lipase. The analyses using ovarian RNA revealed the suppression of gene expression for enzymes involved in steroidogenesis including Cyp11A, Cyp19, steroidogenic acute regulatory protein and high-density lipoprotein receptor, but the Cyp17 expression was evidently induced. Consistent with the suppression of Cyp19 mRNA expression, the aromatase activity in the ovary was dose-dependently inhibited, resulting in significant decreases in the uterine size and bone mineral density. When PPARa null mice were treated with dietary fenofibrate, neither hepatomegaly nor inhibition of ovarian aromatase activity was observed, rather the activity was enhanced. These results demonstrate that fenofibrate inhibits ovarian estrogen synthesis by suppressing the mRNA expressions and that functional PPARa is indispensable for the inhibitory action of the agent in vivo.
Revised on October 28, 2002
Accepted on October 29, 2002
Fenofibrate, a ligand for PPAR
, inhibits aromatase cytochrome P450 expression in the ovary of mouse
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