The peroxisome proliferator-activated receptors (PPARs) are members of the
nuclear hormone receptor subfamily of transcription factors. PPARs form
heterodimers with retinoid X receptors and these heterodimers regulate transcription
of various genes. There are 3 known subtypes of PPARs, PPAR-alpha, PPAR-delta,
and PPAR-gamma.
NCBI Summary:
Peroxisome proliferators are a diverse group of chemicals which include hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers, and are so called because they induce an increase in the size and number of peroxisomes. Peroxisomes are subcellular organelles found in plants and animals, and contain enzymes for respiration, cholesterol and lipid metabolism. Infact, the fibrate class of hypolipidemic drugs is used to reduce triglycerides and cholesterol in patients with hyperlipidemia, a major risk factor for coronary heart disease. The action of peroxisome proliferators is thought to be mediated via specific receptors belonging to the steroid hormone receptor superfamily, called PPARs. Thus far, four closely related subtypes, alpha, beta, gamma and delta, have been identified. The subtype PPAR-alpha, encoded by PPARA, is a nuclear transcription factor. Upon activation by peroxisome proliferators, it modulates the expression of target genes involved in lipid metabolism, suggesting a role for PPAR-alpha in lipid homeostasis.
General function
Receptor, DNA binding, Transcription factor
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Cellular localization
Nuclear
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Ovarian function
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Expression regulated by
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Ovarian localization
Granulosa, Theca, Stromal cells
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Komar CM et al 2001 et al reported the expression and localization of PPARs in the rat ovary during
follicular development and the periovulatory period.
PPARs are a family of nuclear hormone receptors involved in various processes
that could influence ovarian function. The authors investigated the cellular localization and
expression of PPARs during follicular development in ovarian tissue collected
from rats 0, 6, 12, 24, and 48 h post-PMSG. A second group of animals received
human CG (hCG) 48 h post-PMSG. Their ovaries were removed 0, 4, 8, 12, and
24 h post-hCG to study the periovulatory period. mRNAs corresponding to the
PPAR isotypes (alpha, delta, and gamma) were localized by in situ hybridization.
Changes in the levels of mRNA for the PPARs were determined by ribonuclease
protection assays. mRNAs
for PPARalpha and delta were located primarily in theca and stroma, and their
levels did not change during the intervals studied. These data suggest that PPARgamma is involved in follicular
development, has a negative influence on the luteinization of granulosa cells,
and/or regulates the periovulatory shift in steroid production. The more general
and steady expression of PPARs alpha and delta indicate that they may play a role
in basal ovarian function.
Follicle stages
Antral, Preovulatory
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Lovekamp-Swan T, et al reported the dual activation of PPARalpha and PPARgamma by mono-(2-ethylhexyl)
phthalate in rat ovarian granulosa cells.
Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid metabolism and
cell differentiation. The plasticizer di-(2-ethylhexyl) phthalate is a peroxisome proliferator, and its
active metabolite mono-(2-ethylhexyl) phthalate (MEHP) activates PPARalpha and PPARgamma in
cell transactivation assays. MEHP is a female reproductive toxicant and decreases activity, mRNA,
and protein levels of aromatase, the rate-limiting enzyme that converts testosterone to estradiol in
ovarian granulosa cells. To test the hypothesis that MEHP suppresses aromatase through PPAR
pathways, granulosa cells were cultured with MEHP (50 &mgr;M) or selective activators of
PPARgamma or PPARalpha for 48 h and gene expression was analyzed by real time RT-PCR. Both
PPARalpha and PPARgamma activators significantly decreased aromatase mRNA and estradiol
production like MEHP. The PPARgamma-selective antagonist GR 259662 partially blocked the
suppression of aromatase by MEHP, suggesting that MEHP acts through PPARgamma, but not
exclusively. MEHP and the PPARalpha-selective agonist GW 327647 induced expression of
17beta-hydroxysteroid dehydrogenase IV, a known PPARalpha-regulated gene, and induction was
maintained with addition of the PPARgamma-selective antagonist. PPARalpha-selective activation
also induced expression of aryl hydrocarbon receptor (AhR), CYP1B1, and epoxide hydrolase in
the granulosa cell. These data support a model in which MEHP activates both PPARalpha and
PPARgamma to suppress aromatase and alter other genes related to metabolism and differentiation
in the granulosa cell.