Fenofibrate,a ligand for PPARα, inhibits aromatase cytochrome P450 expression in the ovary of mouse

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Peroxisome proliferator-activated receptors(PPARs) play important roles in the metabolic regulationof lipids including steroids. In this study, weinvestigated whether fenofibrate, a ligand for PPARα, couldinfluence estrogen synthesis in vivo in the ovary of mice.As reported, chronic treatment of C57BL6/J female mice withvarious amounts of fenofibrate as a diet reduced the serumtriglycerides level and induced hepatomegaly in adose-dependent manner. Northern blot analyses usinghepatic RNA confirmed the induction of classicalPPARα-target genes including acyl-CoA oxidase andlipoprotein lipase. The analyses using ovarian RNArevealed the suppression of gene expression for enzymesinvolved in steroidogenesis including Cyp11A, Cyp19,steroidogenic acute regulatory protein and high-densitylipoprotein receptor, but the Cyp17 expression wasevidently induced. Consistent with the suppression ofCyp19 mRNA expression, the aromatase activity in the ovarywas dose-dependently inhibited, resulting in significantdecreases in the uterine size and bone mineral density.When PPARα null mice were treated with dietary fenofibrate,neither hepatomegaly nor inhibition of ovarian aromataseactivity was observed, rather the activity was enhanced.These results demonstrate that fenofibrate inhibitsovarian estrogen synthesis by suppressing the mRNAexpressions and that functional PPARα is indispensable forthe inhibitory action of the agent in vivo.