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Journal of Lipid Research, Vol. 44, 265-270, February 2003
Copyright © 2003 by Lipid Research, Inc.

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

Katsumi Toda^1,*, Teruhiko Okada, Chisata Miyaura^** and Toshiji Saibara

^* Departments of Medical Chemistry, Kochi Medical School, Nankoku, Kochi 783-8505, Japan
Anatomy, Kochi Medical School, Nankoku, Kochi 783-8505, Japan
Internal Medicine, Kochi Medical School, Nankoku, Kochi 783-8505, Japan
^** Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan

Published, JLR Papers in Press, November 4, 2002. DOI 10.1194/jlr.M200327-JLR200

¹ To whom correspondence should be addressed. e-mail: todak{at}kochi-ms.ac.jp

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
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 PPAR, 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 PPAR-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 PPAR 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 PPAR is indispensable for the inhibitory action of the agent in vivo.

Supplementary key words peroxisome proliferator-activated receptors • fenofibrate • aromatase • estrogen

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Fibrates and their derivatives (bezafibrate, fenofibrate, clofibrate, and clinofibrate) constitute a group of hypolipidemic agents that are widely used in the treatment of hypertriglyceridemia and combined hyperlipidemia, being particularly effective in lowering the plasma triglyceride and cholesterol levels (1, 2).

Administration of fibrates to rodents results in numerous hepatic alterations, including hepatomegaly, an increase in the number and size of peroxisomes, and an increase in the expression of genes encoding peroxisomal, mitochondrial, and microsomal fatty acid-metabolizing enzymes. These alterations in the liver cause reduction of lipid levels in the serum as well as in adipose tissues (3). Previously, we reported that bezafibrate or fenofibrate was effective in restoring hepatic steatosis due to estrogen-insufficiency in mice (4–6).

The pharmacological actions of fibrates have been found to be mediated through activation of the peroxisome proliferator-activated receptor (PPAR), a member of the nuclear hormone receptor superfamily (3). Activated PPAR binds as a heterodimer with the retinoid X receptor to a peroxisome proliferator-response element located in the promoter region of target genes, which results in transcriptional activation of the target (7) genes (8).

Apart from the genes coding for enzymes involved in fatty-acid metabolism, recent studies have demonstrated that activated PPAR regulates the expression of genes for enzymes involved in steroid metabolism. Those include 17ß-hydroxysteroid dehydrogenase IV, 11ß-hydroxysteroid dehydrogenase I, and 3ß-hydroxysteroid dehydrogenase V (9–11). Furthermore, progesterone production in human choriocarcinoma JEG-3 cells (12) and in Leydig cells (13) is reported to be inhibited by a PPAR-mediated pathway.

To better understand the molecular mechanisms of the pleiotropic responses induced by activated PPAR, we investigated its effects on the ovarian estrogen synthesis in vivo using mice. The data demonstrate that fenofibrate inhibits aromatase activity by suppressing the mRNA expression in a dose-dependent manner, and further that functional PPAR is required for the agent to exhibit inhibitory action in vivo.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Materials
A standard rodent chow (NMF) was obtained from Oriental Yeast (Tokyo, Japan). A kit for the measurement of triglyceride was purchased from Nissui Ltd. (Tokyo Japan). Fenofibrate was from Sigma-Aldrich Japan (Tokyo, Japan). ISOGEN was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). A Zeta-Probe blotting membrane was obtained from Bio-Rad (Hercules, CA). [-³²P]dCTP was purchased from ICN Biomedicals, Inc (Costa Mesa, CA). pBluescript SKII(-) was obtained from Stratagene (La Jolla, CA). All other chemicals were of analytical grade and obtained commercially.

Animals
Animal care and experiments were carried out in accordance with institutional animal regulations. PPAR null mice (14) were obtained from the Jackson Laboratory. C57BL6/J and PPAR null female mice were maintained on a 12 h light/dark cycle at 22–25°C and given water and rodent chow diet with or without fenofibrate ad libitum.

The chow diets supplemented with fenofibrate were prepared by impregnation with fenofibrate, which was dissolved in acetone as described previously (15). C57BL6/J female mice at 7 weeks of age were divided into five diet groups and fed a diet containing various amounts of fenofibrate for 4 weeks: 0% (n = 6), 0.005% (n = 11), 0.02% (n = 14), 0.1% (n = 19), and 0.4% (n = 13). PPAR null female mice at the same age were fed a normal diet with 0% (n = 5) or 0.1% (n = 5) fenofibrate for 4 weeks and used for analysis.

Aromatase activity
Four to six ovaries were used to prepare microsomal fractions (16). Aromatase activity in the fractions was measured by a tritiated water-release assay using 1ß-[³H]androst-4-ene-3,17-dione as a substrate as described previously (17). An inhibitor of aromatase, 4-androsten-4-ol-3,17-dione, was included at 10 µM. Aromatase activity was expressed as picomoles of [³H]water released per mg protein per h.

Histological examination
Ovaries from the mice treated with fenofibrate were fixed in a solution of 10% buffered formalin for 24 h, dehydrated in graded ethanol, and embedded in paraffin. Sections were cut 4 µm thick and stained with hematoxylin-eosin.

Measurement of plasma triglyceride concentration
Plasma was prepared from the blood samples collected from the tail vein of mice after they were fasted for 5 h. Concentrations of triglyceride were measured by colorimetric methods using 10 µl of the plasma with a kit.

Northern blots
Total RNA was prepared from the livers and ovaries using ISOGEN. Equal aliquots of total RNA (15 µg) were denatured with formaldehyde and formamide, subjected to electrophoresis in a 1.0% agarose gel, and transferred to a blotting membrane for hybridization (18). cDNA probes were prepared by PCR amplification using oligo d(T)-primed cDNA derived from ovarian RNA or hepatic RNA as a template with the following sets of primers: P450scc (CYP11A) (a 1,273-bp fragment with sense primer: 5'-TACGTGGCAGGGTCCAGTGCTGAGT-3', and antisense primer: 5'-GAAGTGGGTGGTATTTTGGCTTTTT-3'), P450₁₇ (CYP17) (a 407-bp fragment with sense primer: 5'-TGGTGCACAATCCTGAGGTG-3', and antisense primer: 5'-AAAGGGTCGATCAGAAAGACCACCTTGGGG-3'), HDL receptor (a 604-bp fragment with sense primer: 5'-CCATGAAGCTGACCTACAACGAATCAA-3', and antisense primer: 5'-TCCTGGGAGCCCTTTTTACTACCACTC-3'), steroidogenic acute regulatory protein (StAR) (a 484-bp fragment with sense primer: 5'-AAGCCAGCAGGAGAACGGGGACGAA-3', and antisense primer: 5'-TAGGACCTGGTTGATGATTGTCTTC-3'), PPAR (a 720-bp fragment with sense primer: 5'-CCTGTCTGTCGGGATGTCACACAATGC-3', and antisense primer: 5'-TGCAACTTCTCAATGTAGCCTATGTTT-3'), lipoprotein lipase (LPL) (a 1,101-bp fragment with sense primer: 5'-GGCCGCAGCAGACGCAGGAAGAGATTT-3', and antisense primer: 5'-AAGAAGGAGTAGGTTTTATTTGTGGAA-3'), and 17ß-hydroxysteroid dehydrogenase (17ß-HSD) (a 765-bp fragment with sense primer: 5'-AAATAGCCATAGATGCTGGTTTCC-3', and antisense primer: 5'-TCATGTCCTCTGAAGTCAACTGAA-3'). The amplified products were cloned into the EcoRV site of pBluescript SKII(-). The cDNA fragments for acyl-CoA oxidase, P450_arom(CYP19), FSH receptor, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were prepared as described previously (4, 19). The cDNA probes were labeled with [-³²P]dCTP using a Klenow fragment. The filters were hybridized with the indicated ³²P-labeled probes (1 x 10⁶ cpm/ml) for 12 h at 42°C, washed three times with 0.1% (w/v) SDS/0.1x SSC at 50°C for 30 min, and exposed at -80°C to Fuji X-ray film (Fuji Photofilm Inc.) with intensifying screens for 12–36 h. The quantification of the signals was done with BAS2000 (Fujifilm Inc. Tokyo, Japan). The results were normalized to the signal generated from GAPDH mRNA.

Radiographic analysis of the femur
Radiographs of the femurs were taken with a soft X-ray generator (model CMB-2; SOFTEX, Tokyo, Japan) (20). The bone mineral density (BMD) of the femurs was measured using a dual X-ray absorptiometer (model DCS-600R; Aloka, Tokyo, Japan), as reported previously (20).

Statistic analysis
Data are expressed as the means ± SEM. The significance of the differences was analyzed using the Student's t-test employing InStat software (GraphPad Software, Inc., San Diego, CA). A P value less than 0.05 was considered significant.

	RESULTS

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Effects of fenofibrate on gene expression involved in hepatic fatty acid metabolism
When wild-type female mice were fed a chow diet containing 0%, 0.005%, 0.02%, 0.1%, and 0.4% of fenofibrate for 4 weeks, the liver-body weight ratio increased from 0.052, 0.051, 0.064 (P < 0.02, vs. 0%), 0.103 (P < 0.001), and 0.138 (P < 0.001), respectively, showing induction of dose-dependent hepatomegaly. Furthermore, fenofibrate treatment resulted in a significant decrease in the fasted serum levels of triglycerides from 29.8 ± 1.7 mg/dl (0%) to 15.7 ± 3.3 mg/dl (0.005%, P < 0.02 vs. 0%), 9.8 ± 0.8 mg/dl (0.02%, P < 0.001 vs. 0%), 13.9 ± 1.5 mg/dl (0.1%, P < 0.001 vs. 0%), and 11.9 ± 1.4 mg/dl (0.4%, P < 0.001 vs. 0%). The effects of fenofibrate on the liver were also examined by measuring the mRNA expression of genes for acyl-CoA oxidase, LPL, 17ß-HSD, and HDL receptor (Fig. 1) . The expression level of acyl-CoA oxidase and LPL was dose-dependently elevated in the mice treated with fenofibrate. In contrast, the expression of 17ß-HSD, which participates in the metabolism of steroids (21), was suppressed in a dose-dependent manner. Fenofibrate did not influence the expression of HDL receptor in the liver. These hepatic effects of fenofibrate are in good agreement with earlier studies (8, 22).

View larger version (54K): [in this window] [in a new window]   Fig. 1. Alterations in the gene expression in the liver of mice treated with fenofibrate. The expression of acyl-CoA oxidase, LPL, HDL receptor, 17ß-HSD, and GAPDH mRNAs was analyzed by Northern blot hybridization using 15 µg of total RNA from the livers of C57BL6/J female mice. The mice were fed a chow diet supplemented with 0% (lane 1), 0.005% (lane 2), 0.02% (lane 3), 0.1% (lane 4), 0.4% (lane 5) fenofibrate from 7 weeks of age for 4 weeks.

View larger version (48K): [in this window] [in a new window]   Fig. 2. Alterations in the gene expression in the ovaries of mice treated with fenofibrate. The expression of CYP11A, CYP17, CYP19, HDL receptor, StAR, PPAR, FSH receptor, and GAPDH mRNAs was analyzed by Northern blot hybridization using 15 µg of total RNA from the ovaries of C57BL6/J female mice. The mice were fed a chow diet supplemented with 0% (lane 1), 0.005% (lane 2), 0.02% (lane 3), 0.1% (lane 4), 0.4% (lane 5) fenofibrate from 7 weeks of age for 4 weeks. The number at the top of each lane represents the mean of expression level of the gene relative to that of the untreated mice. The quantification of the expression levels was made in two independent experiments.

View larger version (28K): [in this window] [in a new window]   Fig. 3. Alterations in the ovarian aromatase activity, uterine size, and bone mineral density. A: The female mice were fed a diet containing 0% (lane 1), 0.005% (lane 2), 0.02% (lane 3), 0.1% (lane 4), 0.4% (lane 5) fenofibrate from 7 weeks of age for 4 weeks. The aromatase activity was measured using the tritiated water-releasing method. Microsomal fractions prepared from the ovaries were incubated with 1ß-[3H]androst-4-ene-3,17-dione,[1ß-3H(N)] at 37°C for 1 h in the absence (open bar) or presence (closed bar) of 10 µM 4-androsten-4-ol-3,17-dione, an aromatase inhibitor. The radioactivity released from the substrate in the form of H2O was determined. The activity is expressed as picomoles of tritiated water released/mg protein/h. Each bar represents the mean ± SEM of three experiments. B: Effects of dietary fenofibrate on uterine weight were measured. C: Bone mineral density (BMD) in the total area of the femur was measured. The data are expressed as the mean ± SEM. Significantly different from untreated mice. **P < 0.02, *** P < 0.001.

View larger version (96K): [in this window] [in a new window]   Fig. 4. Micrograph of ovaries of mice treated with fenofibrate. The mice were treated with 0% (A, B), 0.02% (C, D), and 0.4% (E, F) fenofibrate from 7 weeks of age for 4 weeks. The ovaries were collected and processed for histological analysis. The sections were stained with hematoxylin-eosin. Typical corpus lutea (stars) were observed in the control ovary (A and B) but not in the ovary of mice treated with 0.4% fenofibrate (E and F). Furthermore, many atretic follicles were observed in the ovaries treated with 0.4% fenofibrate. The ovaries of mice treated with 0.02% fenofibrate showed intermediate values between those shown in A and E. Bars, 500 µm in A, and 10 µm in B.

Effects of fenofibrate on the liver, uterus, and ovary of PPAR null mice
PPAR null mice were similarly treated with 0.1% fenofibrate to examine whether the effects observed in the wild-type mice were exerted through the activation of the PPAR pathway or not. The liver-body weight ratios in the control and fenofibrate-treated mice were 0.044 ± 0.004 and 0.04 ± 0.001 (n = 5), respectively, indicating no induction of hepatomegaly (Fig. 5A) . The uterine weights were 111.3 ± 27.9 mg and 162.2 ± 34.8 mg for the control and treated mice, respectively, although the difference was not significant (Fig. 5B). Unexpectedly, the aromatase activity in the ovaries of the PPAR null mice was stimulated 5.5-fold over the control level by dietary fenofibrate (Fig. 5C). The induction of steroidogenesis in PPAR null mice by agonists for PPAR has been reported recently (13). Nevertheless, our present findings strongly indicate that functional PPAR is required for fenofibrate to inhibit the aromatase activity in the ovary of mice.

View larger version (18K): [in this window] [in a new window]   Fig. 5. Effects of dietary fenofibrate on PPAR null mice. The PPAR null female mice at 7 weeks of age were fed a diet containing 0% or 0.1% fenofibrate for 4 weeks. A: The ratio of liver-body weight, an indicator of hepatomegaly, was determined. B: Uterine weights of mice treated with fenofibrate were measured. C: Aromatase activity in the ovarian microsomal fractions was measured in the absence (open bar) or presence (closed bar) of 10 µM 4-andro-sten-4-ol-3,17-dione, an aromatase inhibitor. The radioactivity released from the substrate in the form of H2O was determined. The activity is expressed as picomoles of tritiated water released/mg protein/h. Each bar represents the mean ± SEM of three experiments. Significantly different from untreated mice **P < 0.02.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Agonists of PPAR such as prostaglandin J2 or ciglitazone were shown to stimulate secretion of 17ß-estradiol in cultured rat granulosa cells (26). Nonetheless, the stimulatory effect of the agonists on the estrogen biosynthesis is still controversial, as selective ligands for PPAR such as thiazolidinedione inhibited transcription of the CYP19 gene in cultured human adipose stromal cells (27) and in human ovarian granulosa cells (28). Furthermore, a study employing in situ hybridization demonstrated that PPAR is a major subtype of PPARs expressed in the rat ovary (26). These studies, therefore, imply that fenofibrate might inhibit the mRNA expression and activity of aromatase not through the activation of PPAR, but PPAR. However, the results obtained with the PPAR null mice indicate that functional PPAR is obligatory for the inhibitory actions of fenofibrate in vivo. It remains to be clarified whether the drug acts directly on the ovary. A recent study has provided evidence to support the direct action of activated PPAR on steroidogenic cells such as Leydig cells, where PPAR inhibits steroidogenesis through suppression of the transport of cholesterol into the mitochondria (13). Alternatively, fenofibrate possibly modifies the hypothalamic-pituitary functions to inhibit the production of gonadotropin, which in turn causes the inhibition of estrogen synthesis in the ovary. The importance of PPAR in the transcriptional regulation in the pituitary cells has been reported in an in vitro study (29). Other indirect effects of fenofibrate and/or its metabolized products on certain signaling molecules that might interfere with the transcription of Cyp19 in the ovary could also account for the phenomenon. Likewise, this possible indirect action of fenofibrate might explain the unexpected response of PPAR null mice, in which the aromatase activity is significantly enhanced by the drug. As diminution in uterine size and loss of BMD are characteristic manifestations of estrogen insufficiency, as occurred in aromatase gene-knockout (ArKO) mice (19, 20), we assume that the symptoms observed in the mice treated with fenofibrate are ascribed to a suppression in estrogen synthesis. Nevertheless, it is possible that the drug acts directly on the uterus and bone, because the diminution in uterine size and loss of BMD are also observed in ArKO mice treated with fenofibrate (K. Toda, unpublished observations).

Administration of fibrates such as bezafibrate is proposed to be beneficial in continuing tamoxifen treatment for obese early breast cancer patients (30), because adjuvant tamoxifen often induces severe liver steatosis and nonalcoholic steatohepatitis (31). In addition, tamoxifen is suggested to be an intrinsic estrogenic agonist, and a minimal but evident risk of endometrial cancer has been reported with adjuvant tamoxifen (32). Our present study supports the beneficial effects of a coadministration of PPAR activators with antiestrogenic drugs or aromatase inhibitors for the treatment of estrogen-dependent diseases, because they not only activate fatty acid ß-oxidation in the liver, but also inhibit estrogen synthesis.

Apart from the clinical aspects, we should point out the possible disruption of the endocrine system by unintended activation of PPAR, as ligands for PPAR are found in diverse classes of chemical compounds, including commercially used plasticizers (e.g., phthalate esters), industrial solvents used as surfactants or wetting agents (e.g., trichloroethylene), herbicides (e.g., perfluorodecanoic acid), and naturally occurring chemicals (e.g., phytanic acid) (33, 34). Thus, unlimited exposure to these compounds might induce the suppression of estrogen synthesis, which results in unexpected side effects in vivo, including detrimental effects on the reproductive system.

	ACKNOWLEDGMENTS

 
This work was partially supported by grants (13670145 and 13670524 for K.T. and T.S., respectively) from the Japan Society for the Promotion of Science, and from the Sumitomo Foundation to K.T.

Manuscript received August 16, 2002 and in revised form October 28, 2002.

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