Involvement of peroxisome proliferator-activated receptor γ in gonadal steroidogenesis and steroidogenic acute regulatory protein expression

2009 ◽  
Vol 21 (7) ◽  
pp. 909 ◽  
Author(s):  
Mariusz P. Kowalewski ◽  
Matthew T. Dyson ◽  
Pulak R. Manna ◽  
Douglas M. Stocco
Keyword(s):  
Granulosa Cells ◽  
Promoter Activity ◽  
Combined Treatment ◽  
Regulatory Protein ◽  
Steroidogenic Acute Regulatory Protein ◽  
Peroxisome Proliferator ◽  
Activator Protein 1 ◽  
Dibutyryl Camp ◽  
Peroxisome Proliferator Activated Receptor ◽  
Steroidogenic Acute Regulatory

Peroxisome proliferator-activated receptor (PPAR) γ belongs to the PPAR family of nuclear transcription factors whose ligands, such as eicosanoids, fatty acids and prostaglandins, are known to affect gonadal function. Although several of these enhance the expression of the steroidogenic acute regulatory protein (STAR) and steroid production, the role of PPARγ in regulating STAR-mediated steroidogenesis remains unclear. In the present study, we used ciglitazone to selectively activate PPARγ and examine its role in STAR-mediated steroidogenesis in immortalised KK1 mouse granulosa cells and MA-10 mouse Leydig tumour cells. Cotreatment with both dibutyryl-cAMP and ciglitazone revealed a dose-dependent, significant increase in progesterone synthesis, Star promoter activity, Star mRNA and STAR protein relative to either compound alone. The overexpression of PPARγ further increased Star-promoter activity. The ciglitazone-induced activity of the Star-promoter appears to be mediated through the cAMP-response element half-sites located within its proximal 151 bp. Combined treatment with ciglitazone and dibutyryl-cAMP significantly increased the expression and activity of transcriptional pathways impacted by the activator protein-1 family member c-JUN. The present study demonstrates that ciglitazone and dibutyryl-cAMP synergistically enhance STAR expression in MA-10 and KK1 cells. Ciglitazone-activated PPARγ appears to increase the sensitivity of Leydig and granulosa cells to cAMP stimulation, possibly via upregulation of c-JUN expression.

Rosiglitazone increases expression of steroidogenic acute regulatory protein and progesterone production through PPARγ–EGFR–ERK1/2 in human cumulus granulosa cells

2019 ◽  
Vol 31 (11) ◽  
pp. 1647
Author(s):  
Kristina Pogrmic-Majkic ◽  
Gordana Kosanin ◽  
Dragana Samardzija Nenadov ◽  
Svetlana Fa ◽  
Bojana Stanic ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Regulatory Protein ◽  
Growth Factor Receptor ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Progesterone Production ◽  
Extracellular Signal ◽  
Epidermal Growth ◽  
Steroidogenic Acute Regulatory

The mechanism by which rosiglitazone (ROSI: a thiazolidinedione (TZD)) affects steroid production in undifferentiated human granulosa cells is not known. In this study, cultured human cumulus granulosa cells were exposed to ROSI and pharmacological inhibitors of the extracellular signal-regulated kinase 1/2 (ERK1/2), epidermal growth factor receptor (EGFR) and peroxisome proliferator-activated receptor gamma (PPARγ) signalling pathways. Expression of progesterone biosynthetic enzymes, PPARγ and PPARα, progesterone production and ERK1/2 activation were analysed. After 48h, 30μM ROSI increased STAR, 3βHSD and PPARγ mRNA and elevated progesterone production in human cumulus granulosa cells. Addition of ERK1/2 (U0126), EGFR (AG1478) and PPARγ (GW9662) inhibitors prevented the ROSI-induced STAR mRNA expression and progesterone production after 48h. Inhibition of PPARγ, but not EGFR or ERK1/2, decreased the PPARγ mRNA levels induced by ROSI in human cumulus granulosa cells after 48h. On the other hand, U0126 and GW9662 prevented the ROSI-induced increase in PPARγ transcripts after 6h. Western blot analysis showed that ROSI induced a rapid ERK1/2 activation, which was prevented by inhibition of ERK1/2, EGFR and PPARγ in human cumulus granulosa cells. Overall, these data suggested that PPARγ, EGFR and ERK1/2 were involved in the stimulatory effect of ROSI on STAR expression and progesterone production in undifferentiated human cumulus granulosa cells.

scholarly journals Crucial Role of Estrogen Receptor-α Interaction with Transcription Coregulators in Follicle-Stimulating Hormone and Transforming Growth Factor β1 Up-Regulation of Steroidogenesis in Rat Ovarian Granulosa Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4658-4668 ◽  
Author(s):  
Yun-Ju Chen ◽  
Ming-Ting Lee ◽  
Hsiao-Chun Yao ◽  
Pei-Wen Hsiao ◽  
Ferng-Chun Ke ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Granulosa Cells ◽  
Transforming Growth Factor ◽  
Regulatory Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ovarian Granulosa Cells ◽  
Progesterone Production ◽  
17Β Estradiol ◽  
Histone Acetylases

This study was to explore estrogen receptor (ER) involvement in FSH and TGFβ1-stimulated steroidogenesis in rat ovarian granulosa cells. We first determined the specific involvement of ERα and ERβ in the process, and then investigated the molecular interaction of ERα and transcription coregulators in FSH and TGFβ1 up-regulation of steroidogenic gene expression. Primary culture of ovarian granulosa cells from antral follicles of gonadotropin-primed immature rats was used. Interestingly, a selective ERα antagonist methyl-piperidino-pyrazole (MPP) [like ER antagonist ICI-182,780 (ICI)] decreased FSH ± TGFβ1-stimulated progesterone production, whereas an androgen receptor antagonist hydroxyflutamide and particularly a selective ERβ antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo [1,5-a] pyrimidin-3-yl] phenol had no significant effect. Consistent with this, a selective ERβ agonist diarylpropionitrile (unlike 17β-estradiol) also had no effect on FSH ± TGFβ1-stimulated progesterone production. Furthermore, a selective ERα agonist 4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (like 17β-estradiol) enhanced FSH-stimulated progesterone production, and this was abolished by pretreatment with MPP. Immunoblotting and chromatin immunoprecipitation analyses indicate that MPP/ICI suppression of FSH ± TGFβ1 action is partly attributed to the reduced ERα-mediated expression of Hsd3b and Cyp11a1 genes, but not steroidogenic acute regulatory protein. Furthermore, FSH ± TGFβ1 increased ERα association with histone acetylases (CBP and SRC-1) and coactivator of peroxisome proliferator-activated receptor γ (PGC-1α), and MPP/ICI dramatically reduced these interactions. In addition, FSH ± TGFβ1 increased CBP, SRC-1, and PGC-1α binding to Hsd3b and Cyp11a1 genes. Together, we demonstrate for the first time that ERα interaction with transcription coregulators, histone acetylases (CBP/SRC-1), and PGC-1α is crucial to FSH and TGFβ1-up-regulated expression of Hsd3b and Cyp11a1, and, thus, progesterone production in rat ovarian granulosa cells.

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