Fenofibrate, a ligand for PPARalpha, inhibits aromatase cytochrome P450 expression in the ovary of mouse.
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 PPARalpha, 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 PPARalpha-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 HDL 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 PPARalpha 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 PPARalpha is indispensable for the inhibitory action of the agent in vivo.
Toda
Katsumi
K
Department of Medical Chemistry, Kochi Medical School, Nankoku, Kochi 783-8505, Japan. todak@kochi-ms.ac.jp
Okada
Teruhiko
T
Miyaura
Chisata
C
Saibara
Toshiji
T
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins; D004967:Estrogens / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging; D011345:Fenofibrate / Q000378:metabolism*; D005786:Gene Expression Regulation; D000960:Hypolipidemic Agents / Q000378:metabolism*; D008024:Ligands; D008075:Lipoproteins, HDL; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000166:cytology / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D011859:Radiography; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014599:Uterus / Q000033:anatomy & histology / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
D002352:Carrier Proteins; D004967:Estrogens; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D008024:Ligands; D008075:Lipoproteins, HDL; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018110:Receptors, Lipoprotein; D014157:Transcription Factors; C031616:high density lipoprotein receptors; D000098682:Steroidogenic Acute Regulatory Protein; C075197:high density lipoprotein binding protein; D001141:Aromatase; D011345:Fenofibrate