Feedback Inhibition of Steroidogenic Acute Regulatory Protein Expression in Vitro and in Vivo by Androgens

Christopher P. Houk, Elliot J. Pearson, Nina Martinelle, Patricia K. Donahoe, Jose Teixeira

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Müllerian-inhibiting substance (MIS) reduces testosterone synthesis in Leydig cells by inhibiting cytochrome P450C17 hydroxylase/C17-20 lyase expression. However, in mouse Leydig MA-10 cells, MIS also enhances the cAMP-induced expression of mRNA for steroidogenic acute regulatory protein (StAR), which transports cholesterol to the inner mitochondrial membrane for conversion to pregnenolone. We hypothesized that the MIS-induced StAR expression is the indirect result of reduced testosterone synthesis in Leydig cells caused by MIS. We show that, in addition to MIS, flutamide, an androgen receptor antagonist, enhanced StAR mRNA expression when added to cAMP-treated MA-10 cells, whereas dihydrotestosterone, a potent androgen receptor agonist, attenuated these responses. Progesterone, dexamethasone, and estradiol also inhibited StAR mRNA expression. Addition of MIS to cAMP-treated MA-10 cells transfected with a StAR-promoter luciferase reporter resulted in increased StAR promoter activity over cAMP alone; this effect was inhibited by dihydrotestosterone, suggesting that androgens inhibit StAR mRNA expression at the transcriptional level. Androgen-mediated inhibition of StAR expression was also observed in primary Leydig cell culture and in vivo using both hypophysectomized mice and mice treated with the GnRH antagonist, acyline. These results suggest that the induction of StAR expression by MIS occurs secondary to the MIS-mediated reduction in testosterone synthesis by relieving a hitherto uncharacterized androgen-dependent feedback inhibition on StAR expression. These findings may impact future treatment strategies aimed at reducing androgen; for example, in the treatment of prostatic cancer, antiandrogen treatment might benefit from adjuvant therapy to inhibit StAR expression.

Original languageEnglish (US)
Pages (from-to)1269-1275
Number of pages7
JournalEndocrinology
Volume145
Issue number3
DOIs
StatePublished - Mar 1 2004

Fingerprint

Androgens
Leydig Cells
Testosterone
Messenger RNA
Dihydrotestosterone
In Vitro Techniques
steroidogenic acute regulatory protein
Androgen Receptor Antagonists
Flutamide
Androgen Antagonists
Pregnenolone
Lyases
Primary Cell Culture
Mitochondrial Membranes
Protein Transport
Cytochromes
Mixed Function Oxygenases
Luciferases
Gonadotropin-Releasing Hormone
Dexamethasone

ASJC Scopus subject areas

  • Endocrinology

Cite this

Feedback Inhibition of Steroidogenic Acute Regulatory Protein Expression in Vitro and in Vivo by Androgens. / Houk, Christopher P.; Pearson, Elliot J.; Martinelle, Nina; Donahoe, Patricia K.; Teixeira, Jose.

In: Endocrinology, Vol. 145, No. 3, 01.03.2004, p. 1269-1275.

Research output: Contribution to journalArticle

Houk, Christopher P. ; Pearson, Elliot J. ; Martinelle, Nina ; Donahoe, Patricia K. ; Teixeira, Jose. / Feedback Inhibition of Steroidogenic Acute Regulatory Protein Expression in Vitro and in Vivo by Androgens. In: Endocrinology. 2004 ; Vol. 145, No. 3. pp. 1269-1275.
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