API

Relationship: 395

Title

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demethylation, PPARg promoter leads to reduction in ovarian granulosa cells, Aromatase (Cyp19a1)

Upstream event

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demethylation, PPARg promoter

Downstream event

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reduction in ovarian granulosa cells, Aromatase (Cyp19a1)

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus NCBI
human Homo sapiens Moderate NCBI
mouse Mus musculus Weak NCBI

Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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This KER establishes the link between PPARγ activation and reduced levels of aromatase in ovarian granulosa cells. Aromatase is a key enzyme in steroidogenesis, catalysing the conversion of androgens to estrogens.

Weight of Evidence

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Biological Plausibility

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Peroxisome proliferator-activated receptor γ (PPARγ) is master switch of lipid metabolism and cell differentiation, their role has also been acknowledged in regulation of reproductive function and development [reviewed by (P Froment et al., 2006), (Minge, Robker, & Norman, 2008)]. The PPARs are implicated in regulation of steroidogenesis from in vitro data [reviewed by (Carolyn M Komar, 2005)].

PPARγ involvement in aromatase regulation in granulosa cells

The PPARγ is activated upon the ligand binding in granulosa cells, and then indirectly alters the expression of aromatase, the rate-limiting enzyme in conversion of androgens to estrogens (Kwintkiewicz, Nishi, Yanase, & Giudice, 2010), (Lovekamp-Swan, Jetten, & Davis, 2003), (Mu et al., 2000). The ligands of PPARγ were also shown to regulate other enzymes involved in steroidogenesis (Dupont, Chabrolle, Ramé, Tosca, & Coyral-Castel, 2008). All PPAR isoforms have been detected in both human and rodent ovary [reviewed by (Carolyn M Komar, 2005)]. In female rats the PPARγ have been detected in granulosa cells.


• PPARγ is primarily expressed in the granulosa cells and pre-ovulatory follicles, less strongly in the theca cells and corpus luteum where its expression increases after ovulation and falls after the LH surge, (C M Komar, Braissant, Wahli, & Curry, 2001). In the absence of fertilization or embryo implantation, PPARγ expression decreases as a result of corpus luteum regression (Viergutz, Loehrke, Poehland, Becker, & Kanitz, 2000).

• PPARγ is directly involved in oocyte maturation and ovulation [reviewed by (P Froment et al., 2006)]

Additional studies have shown that PPARγ is active in the ovary (P Froment et al. 2003).

The precise molecular mechanism by which PPARγ regulates aromatase is unclear given the fact that the proximal promoter regulating aromatase expression in the rat ovary does not contain an obvious peroxisome proliferator response element (PPRE) (Young and McPhaul 1997). There are plausible ways by which the PPARγ (as transcriptionally active PPAR:RXR heterodimer) could modify the transcription of aromatase including activation of RXR competition for binding sites on DNA and competition for limiting co-activators required for gene transcription. A new insight in the mechanism of regulation of the aromatase gene and activation of PPAR gamma and RXR was brought by Fan et al proposing disruption of NF-κB interaction with the aromatase promoter (Fan et al. 2005). The authors showed that activation of PPARγ and RXR impaired the interaction between NF-κB and aromatase promoter II and the p65 based transcription in both ovarian and fibroblast cells in a PPARγ-dependent manner (Fan et al. 2005). Studies supporting that hypothesis show that both PPARγ ligand (Troglitazone) and RXR ligand (LG100268) suppress aromatase activity in human granulosa cells (Mu et al. 2000), (Mu et al. 2001) and together causing a greater reduction than either compound alone (Mu et al. 2000).

Another possibility is that PPARγ is able to modify protein–protein interactions involved in the transcription of aromatase. Activation of PPARγ may recruit cofactors away from aromatase to inhibit normal transcription. Further studies are necessary to determine how PPARγ transcriptionally repress aromatase.

Empirical Support for Linkage

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Agonists of PPARγ were shown to also decrease aromatase in human and rodent ovarian cells: Bisphenol A, in vitro, human: (Kwintkiewicz et al., 2010) showing significant PPARγ activation and reduction of aromatase from the same dose (40μM).

MEHP, in vitro , rat: at 50 μM 45% decrease mRNA aromatase (Lovekamp-Swan et al., 2003) DEHP, in vivo , rat: dose dependent increase of PPARγ and reduction of aromatase (300-600mg/kg/day), measured at the same time point (Xu et al., 2010).

The treatment of the granulosa cells with PPARγ ligand (Troglitazone) results in an inhibition of the aromatase protein levels and/or activity in a dose-dependent manner (Mu et al., 2000), (Mu et al., 2001). Table 1 provides the experimental support for the implication of PPARγ in aromatase regulation (limited quantitative and taxonomical aspects are included).

Inhibition studies

The involvement of each PPARγ subtype in the suppression of aromatase by MEHP was shown by Lovekamp-Swan et al. MEHP alone suppressed aromatase by 48% and the PPARγ (GW 347845) agonists alone decreased aromatase by 30 % . As expected, the PPARγ antagonist (GR 259662) completely blocked the suppression of aromatase by the PPARγ-selective agonist (Lovekamp-Swan et al., 2003).

Table 1 summaries the studies and compounds activating PPARγ and causing decrease level of aromatase (in granulosa cells) including limited quantitative and taxonomical aspects. Data for activation of PPARα are also included as it is hypothesised contributing/synergising pathway.


PPAR activation
Aromatase decrease
species
Compound
PPARα binding
PPARγ binding
PPARα activation
PPARγ activation
MEHP
Ki=15µM, (Lapinskas et al., 2005),


Ki=12 µM, (Lapinskas et al., 2005)
AC50=20.1µM, cell free (ToxCastTM Data, n.d.)
LECT=1 µM, HepG cells (Lapinskas et al., 2005)
LECT= 100 μM MCF-7 cells, (Venkata et al., 2006)
LECT= 125 µM, HEK293 cells (Lampen et al., 2003)
EC50 =6.2 µM, COS-1 cells (Hurst and Waxman, 2003)
LECT=0.1 MCF-7 cells, (Venkata et al., 2006)
LECT=25 µM, HepG cells(Lapinskas et al., 2005)
LECT= 65.2 µM, HEK293 cells (Lampen et al., 2003)
AC50=37.1 µM, HepG2 cells (ToxCastTM Data, n.d.)

At 167µM decrease mRNA, granulosa-lutein cells (Reinsberg et al., 2009)

human
n.f.
n.f.
LECT= 65.2 µM, CHO cells (Lampen et al., 2003)
EC50 =0.6 μM COS-1 cells (Hurst and Waxman, 2003)
EC50 =10.1 μM, COS-1 cells (Hurst and Waxman, 2003)
LECT= 65.2 µM, CHO cells (Lampen et al., 2003)

At 50 μM 45% decrease mRNA (Lovekamp-Swan et al., 2003)

LECT= 50 μM decrease mRNA, granulosa cells isolated from rats(Lovekamp and Davis, 2001)

rodent
Troglitazone
inactive
n.i.
inactive
EC50 = 0.55 μM (Willson et al., 2000)

At 1 μM 50% activity of aromatase;

At 100 μM 90% ofaromatase activity;

At 100 μM decreased mRNA, in granulosa cancer cells (Mu et al., 2001)

In granulosa cells (Mu et al., 2000)


human
inactive
n.i.
inactive
EC50 = 0.78 μM (Willson et al., 2000),

1 μM, 45%-48 decrease mRNA (Lovekamp-Swan et al., 2003)

rodent
WY-14,643
Ki=9µM, (Lapinskas et al., 2005)
Ki=44µM, (Lapinskas et al., 2005)


human

LECT= 100μM decrease mRNA, granulosa cells isolated from rats (Lovekamp and Davis, 2001)

rodent
tributyltin (TBT)
AC50=0.667 μM in HepG cells (ToxCastTM Data, n.d.)
EC50 range=1-10nM (Grimaldi et al., 2015)
AC50=0.169 μM in HepG cells (ToxCastTM Data, n.d.)

inhibited the aromatase activity inhibition and and decreased mRNA level in KGN cells

(Saitoh et al., 2001)

human
Bisphenol A
AC50=0.667 μM in HepG cells (ToxCastTM Data, n.d.)
LECT=40 μM ( increases PPAR protein levels in KGN ovarian granulosa-like tumor cell line (Kwintkiewicz et al., 2010)
AC50=24.4 μM in HepG cells (PPRE) (ToxCastTM Data, n.d.)

At 60-100 μM aromatase decrease, in KGN ovarian granulosa-like tumor cell line (Kwintkiewicz et al., 2010)

LECT=40 μM luteinized granulosa cells (Kwintkiewicz et al., 2010)

human


Table 1 Table summarising the quantitative relationship between activation of PPAR α&γ and decreased levels of aromatase across the species. AC50- and EC50 - half maximal effective concentration values reported if available, Ki - inhibition constant, LECT- lowest effective concentration tested, WY-14,643, agonist of PPAR alpha, has been shown to activate all 3 isoforms of PPAR, n.f.= not found, n.i.= not investigated.

Uncertainties or Inconsistencies

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There is substantial evidence in literature supporting the KER, however the underlying mechanism are to be investigated, together with other pathways involved in aromatase down regulation. The pattern of the PPARγ expression in ovarian follicles is not steady, unlike expression of PPARs α and δ. This fact adds to the complexity to the interpretation of mechanisms involved in the pathway. The PPARγ is down-regulated in response to the LH surge (C M Komar, Braissant, Wahli, & Curry, 2001), but only in follicles that have responded to the LH surge (Carolyn M Komar & Curry, 2003). Because PPARγ is primarily expressed in granulosa cells, it may influence development of these cells and their ability to support normal oocyte maturation. PPARγ could also potentially affect somatic cell/oocyte communication not only by impacting granulosa cell development, but by direct effects on the oocyte. Modulation of the PPARγ activity/expression in the ovary therefore, could potentially affect oocyte developmental competence. Some evidence implies that the regulatory role of PPARγ might be connected to the other events in estradiol synthesis like the impairment of cholesterol transport to mitochondria (Cui et al., 2002).

PPARα The experimental data supports the parallel involvement of another member of PPAR superfamily of nuclear receptors, PPARα. PPARα was shown to be implicated in the down regulation of aromatase in rat: in vitro (Lovekamp-Swan et al., 2003); in vivo (Xu et al., 2010) and in mice in vivo (Toda, Okada, Miyaura, & Saibara, 2003). The ovarian aromatase promoter contains one half of a PPRE (peroxisome proliferator response element), which is the binding site for steroidogenic factor 1 (SF-1) (Young & McPhaul, 1997). While it is unknown whether PPARα can compete for binding on an incomplete response element, disruption of SF-1 binding to this half site would disrupt normal aromatase transcription. Studies by S. Plummer et al showed that PPARα and SF1 share a common coactivator (S. Plummer, Sharpe, Hallmark, Mahood, & Elcombe, 2007), (S. M. Plummer et al., 2013), CREB-binding protein (CBP), which is present in limiting concentrations (McCampbell, 2000). Binding of CBP to PPARα could therefore starve SF1 a cofactor essential for its transactivation functions. Surprisingly, aromatase levels were increased in ovaries of PPARα-null mice upon treatment with PPARα ligand (Toda et al., 2003).


PPARα was also reported to regulate other enzymes involved in steroidogenesis like: 17 beta-hydroxysteroid dehydrogenase type IV (HSD IV) (Corton et al., 1996), 3 beta-hydroxysteroid dehydrogenase (Wong, Ye, Muhlenkamp, & Gill, 2002) or 11beta-hydroxysteroid dehydrogenase type (Hermanowski-Vosatka et al., 2000). While PPARα/γ activators (like MEHP ) suppress aromatase, they showed no effect on Cholesterol side-chain cleavage enzyme (P450scc) in granulosa cells, demonstrating a more specific effect on steroidogenesis (Lovekamp-Swan et al., 2003). Experiments with PPARα-null mice indicate involvement of the receptor in reproductive toxicity, however cannot be entirely explained by the activation of PPARα mediated pathway as PPARα-null mice remain sensitive to DEHP-mediated reproductive toxicity (Ward et al. 1998), which implies other players including PPARγ. The above evidence supports the involvement of PPARα in regulation of steroidogenesis on its different steps. As PPARα is found primarily in the theca and stroma and the expression of PPARα in granulosa cells is very low (Carolyn M Komar, 2005) therefore it might be involved in steps in steroidogenesis upstream of aromatase.

Retinoid X Receptor (RXR)

Chemicals are able to activate RXR–PPARγ through RXR because this heterodimer interacts poorly with co-repressors in vivo and belongs to the group of so-called ‘permissive’ heterodimers, which can be stimulated by RXR ligands on their own (Germain, Iyer, Zechel, & Gronemeyer, 2002). Studies demonstrated that a PPARγ ligand and/or a RXR ligand decreased the aromatase activity in both cultured human ovarian granulosa cells (Mu et al., 2000), (Mu et al., 2001) and human granulosa-like tumor KGN cells (Kwintkiewicz et al., 2010) and combined treatment causes a greater reduction than either compound alone (Mu et al., 2000), (Mu et al., 2001).

Inconsistencies

No effect on aromatase protein expression was observed after PPARγ ligand (rosiglitazone) treatment in porcine ovarian follicles (Rak-Mardyła & Karpeta, 2014).

Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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See the Table 1.

References

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Synthetic ligand, rosiglitazone stimulates AMP-activated protein kinase (AMPK) and enhances the meiotic resumption of mouse oocytes (Dupont, Reverchon, Cloix, Froment, & Ramé, 2012).