Upstream eventdemethylation, PPARg promoter
Decrease, Aromatase (Cyp19a1)
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
This KER establishes the link between PPAR activation and levels of aromatase. Aromatase is a key enzyme in steroidogenesis, catalysing the conversion of androgens to estrogens.
Evidence Supporting this KER
Peroxisome proliferator-activated receptors (PPARs) are master switches of lipid metabolism and cell differentiation, their role was also acknowledge in regulation of reproductive function and development [reviewed by (Froment et al., 2006)]. In particular PPARγ was found to be critically involved in follicular development, ovulation, maintenance of corpus luteum during pregnancy, and maturation and function of placenta (Barak et al., 1999). The PPARs are implicated in regulation of steroidogenesis in vitro [reviewed by (Carolyn M Komar, 2005)]. The PPARγ is activated upon the ligand binding in granulosa cells, and then indirectly alters the expression of aromatase, rate-limiting enzyme in conversion of androgens to estrogenes (Richards, 1980) and other enzymes involved in steroidogenesis (Dupont, Chabrolle, Ramé, Tosca, & Coyral-Castel, 2008). Moreover there is evidence of implication of another isoform of PPAR in the effect on aromatase, the PPARα (Lovekamp-Swan, Jetten, & Davis, 2003).
In the ovary all PPAR isoforms have been detected in both human and rodent ovary (Braissant, Foufelle, Scotto, Dauça, & Wahli, 1996), (C M Komar, Braissant, Wahli, & Curry, 2001), (Lambe & Tugwood, 1996) reviewed (Carolyn M Komar, 2005). In female rats the PPAR was detected in estradiol producing cells and is involved in the regulation of fertility:
• PPARγ is primarily expressed in the granulosa cells and preovulatory follicles, less strongly expressed in the theca cells and in corpus luteum where it increases after ovulation (its expression falls after the LH surge ) (C M Komar et al., 2001). However, 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 directly involved in oocyte maturation and ovulation [reviewed by (Froment et al., 2006)]. • PPAR α is found primarily in the theca and stroma, the expression of PPARα in granulosa cells is very low [reviewed by (Carolyn M Komar, 2005)] The precise molecular mechanism by which PPAR 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 & McPhaul, 1997). There are plausible ways in which the PPARγ could modify the transcript of aromatase, as transcriptionally active PPAR:RXR heterodimer, this includes: competition for binding sites on DNA and competition for limiting co-activators required for gene transcription. Previous studies show that both PPARγ and RXR ligands alone suppress aromatase activity in human granulosa cells, and combined treatment causes a greater reduction than either compound alone (Mu et al., 2000). The ovarian aromatase promoter contains one half of a PPRE, which is the binding site for steroidogenic factor 1 (SF-1) (Young & McPhaul, 1997). While it is unknown whether PPAR 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, Sharpe, Hallmark, Mahood, & Elcombe, 2007), (S. M. Plummer et al., 2013) showed that PPARα and SF1 share a common coactivator, CREB-binding protein (CBP), which is present in limiting concentrations (McCampbell, 2000). Binding of CBP to PPARα could therefore starve SF1 of a cofactor essential for its transactivation functions. Another possibility is that PPAR is able to modify protein–protein interactions involved in the transcription of aromatase. Activation of PPAR may recruit cofactors away from aromatase to inhibit normal transcription. Further study is necessary to determine how PPAR regulates aromatase transcription.