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

Mariusz P. Kowalewski, Matthew T. Dyson, Pulak R. Manna, Douglas M. Stocco

Research output: Contribution to journalArticle

40 Scopus citations

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 oftranscriptional 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.

Original languageEnglish (US)
Pages (from-to)909-922
Number of pages14
JournalReproduction, Fertility and Development
Volume21
Issue number7
DOIs
StatePublished - 2009

Keywords

  • Granulosa
  • Leydig

ASJC Scopus subject areas

  • Biotechnology
  • Reproductive Medicine
  • Animal Science and Zoology
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Developmental Biology

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