Involvement of peroxisome proliferator-activated receptor γ in gonadal steroidogenesis and steroidogenic acute regulatory protein expression
Mariusz P. Kowalewski A B , Matthew T. Dyson A , Pulak R. Manna A and Douglas M. Stocco A C
+ Author Affiliations
- Author Affiliations
A Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
B Present address: Institute of Veterinary Anatomy, Vetsuisse-Faculty, University of Zurich, Winterthurerstr. 260, CH-8057 Zurich, Switzerland.
C Corresponding author. Email: doug.stocco@ttuhsc.edu
Reproduction, Fertility and Development 21(7) 909-922 https://doi.org/10.1071/RD09027
Submitted: 10 February 2009 Accepted: 15 June 2009 Published: 24 August 2009
Abstract
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.
Additional keywords: granulosa, Leydig.
Acknowledgements
This investigation was supported by National Institutes of Health grant HD-17481 and with funds from the Robert A. Welch Foundation (Grant B1–0028). The skilful technical assistance of Yuping Sun is greatly appreciated.
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