Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells

Israel Ortega, Amanda B. Cress, Donna H. Wong, Jesus A. Villanueva, Anna Sokalska, Benjamin Moeller, Scott D Stanley, Antoni J. Duleba

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, theca-interstitial hyperplasia, and increased androgen production by theca cells. Previously, our group has demonstrated that statins (competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a rate-limiting step of the mevalonate pathway) reduce proliferation of theca-interstitial cells in vitro and decrease serum androgen levels in women with PCOS. The present study evaluated the effect of simvastatin on rat ovarian theca-interstitial cell steroidogenesis. Because actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, the present study also investigated whether steroidogenesis was affected by cell- and mitochondrionpermeable 22-hydroxycholesterol, isoprenylation substrates (farnesyl-pyrophosphate [FPP] and geranylgeranyl-pyrophosphate [GGPP]), as well as selective inhibitors of farnesyltransferase (FTI) and geranylgeranyltransferase (GGTI). Theca-interstitial cells were cultured for 12, 24, and 48 h with or without simvastatin, GGPP, FPP, FTI, GGTI, and/or 22-hydroxycholesterol. Simvastatin decreased androgen levels in a time- and concentration-dependent fashion. This inhibitory effect correlated with a decrease in mRNA levels of Cyp17a1, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 h, GGPP alone and FPP alone had no effect on Cyp17a1 mRNA expression; however, the inhibitory action of simvastatin was partly abrogated by both GGPP and FPP. The present findings indicate that statin-induced reduction of androgen levels is likely due, at least in part, to the inhibition of isoprenylation, resulting in decreased expression of CYP17A1.

Original languageEnglish (US)
Article number20
JournalBiology of Reproduction
Volume86
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Theca Cells
Simvastatin
Androgens
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Gene Expression
Prenylation
Polycystic Ovary Syndrome
Protein Prenylation
Farnesyltranstransferase
Mevalonic Acid
Messenger RNA
Hyperplasia
Oxidoreductases
Cholesterol
geranylgeranyl pyrophosphate
farnesyl pyrophosphate
Enzymes
Serum
Genes

Keywords

  • Androgens/androgen receptor
  • Cell culture
  • CYP17A1
  • Ovarian theca-interstitial cells
  • Ovary
  • Simvastatin
  • Steroid hormones/steroid hormone receptors
  • Steroidogenesis
  • Theca cells

ASJC Scopus subject areas

  • Cell Biology

Cite this

Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells. / Ortega, Israel; Cress, Amanda B.; Wong, Donna H.; Villanueva, Jesus A.; Sokalska, Anna; Moeller, Benjamin; Stanley, Scott D; Duleba, Antoni J.

In: Biology of Reproduction, Vol. 86, No. 1, 20, 01.2012.

Research output: Contribution to journalArticle

Ortega, Israel ; Cress, Amanda B. ; Wong, Donna H. ; Villanueva, Jesus A. ; Sokalska, Anna ; Moeller, Benjamin ; Stanley, Scott D ; Duleba, Antoni J. / Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells. In: Biology of Reproduction. 2012 ; Vol. 86, No. 1.
@article{f2e580955c1b459caf1a171e1a43aa78,
title = "Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells",
abstract = "Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, theca-interstitial hyperplasia, and increased androgen production by theca cells. Previously, our group has demonstrated that statins (competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a rate-limiting step of the mevalonate pathway) reduce proliferation of theca-interstitial cells in vitro and decrease serum androgen levels in women with PCOS. The present study evaluated the effect of simvastatin on rat ovarian theca-interstitial cell steroidogenesis. Because actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, the present study also investigated whether steroidogenesis was affected by cell- and mitochondrionpermeable 22-hydroxycholesterol, isoprenylation substrates (farnesyl-pyrophosphate [FPP] and geranylgeranyl-pyrophosphate [GGPP]), as well as selective inhibitors of farnesyltransferase (FTI) and geranylgeranyltransferase (GGTI). Theca-interstitial cells were cultured for 12, 24, and 48 h with or without simvastatin, GGPP, FPP, FTI, GGTI, and/or 22-hydroxycholesterol. Simvastatin decreased androgen levels in a time- and concentration-dependent fashion. This inhibitory effect correlated with a decrease in mRNA levels of Cyp17a1, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 h, GGPP alone and FPP alone had no effect on Cyp17a1 mRNA expression; however, the inhibitory action of simvastatin was partly abrogated by both GGPP and FPP. The present findings indicate that statin-induced reduction of androgen levels is likely due, at least in part, to the inhibition of isoprenylation, resulting in decreased expression of CYP17A1.",
keywords = "Androgens/androgen receptor, Cell culture, CYP17A1, Ovarian theca-interstitial cells, Ovary, Simvastatin, Steroid hormones/steroid hormone receptors, Steroidogenesis, Theca cells",
author = "Israel Ortega and Cress, {Amanda B.} and Wong, {Donna H.} and Villanueva, {Jesus A.} and Anna Sokalska and Benjamin Moeller and Stanley, {Scott D} and Duleba, {Antoni J.}",
year = "2012",
month = "1",
doi = "10.1095/biolreprod.111.094714",
language = "English (US)",
volume = "86",
journal = "Biology of Reproduction",
issn = "0006-3363",
publisher = "Society for the Study of Reproduction",
number = "1",

}

TY - JOUR

T1 - Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells

AU - Ortega, Israel

AU - Cress, Amanda B.

AU - Wong, Donna H.

AU - Villanueva, Jesus A.

AU - Sokalska, Anna

AU - Moeller, Benjamin

AU - Stanley, Scott D

AU - Duleba, Antoni J.

PY - 2012/1

Y1 - 2012/1

N2 - Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, theca-interstitial hyperplasia, and increased androgen production by theca cells. Previously, our group has demonstrated that statins (competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a rate-limiting step of the mevalonate pathway) reduce proliferation of theca-interstitial cells in vitro and decrease serum androgen levels in women with PCOS. The present study evaluated the effect of simvastatin on rat ovarian theca-interstitial cell steroidogenesis. Because actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, the present study also investigated whether steroidogenesis was affected by cell- and mitochondrionpermeable 22-hydroxycholesterol, isoprenylation substrates (farnesyl-pyrophosphate [FPP] and geranylgeranyl-pyrophosphate [GGPP]), as well as selective inhibitors of farnesyltransferase (FTI) and geranylgeranyltransferase (GGTI). Theca-interstitial cells were cultured for 12, 24, and 48 h with or without simvastatin, GGPP, FPP, FTI, GGTI, and/or 22-hydroxycholesterol. Simvastatin decreased androgen levels in a time- and concentration-dependent fashion. This inhibitory effect correlated with a decrease in mRNA levels of Cyp17a1, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 h, GGPP alone and FPP alone had no effect on Cyp17a1 mRNA expression; however, the inhibitory action of simvastatin was partly abrogated by both GGPP and FPP. The present findings indicate that statin-induced reduction of androgen levels is likely due, at least in part, to the inhibition of isoprenylation, resulting in decreased expression of CYP17A1.

AB - Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, theca-interstitial hyperplasia, and increased androgen production by theca cells. Previously, our group has demonstrated that statins (competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a rate-limiting step of the mevalonate pathway) reduce proliferation of theca-interstitial cells in vitro and decrease serum androgen levels in women with PCOS. The present study evaluated the effect of simvastatin on rat ovarian theca-interstitial cell steroidogenesis. Because actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, the present study also investigated whether steroidogenesis was affected by cell- and mitochondrionpermeable 22-hydroxycholesterol, isoprenylation substrates (farnesyl-pyrophosphate [FPP] and geranylgeranyl-pyrophosphate [GGPP]), as well as selective inhibitors of farnesyltransferase (FTI) and geranylgeranyltransferase (GGTI). Theca-interstitial cells were cultured for 12, 24, and 48 h with or without simvastatin, GGPP, FPP, FTI, GGTI, and/or 22-hydroxycholesterol. Simvastatin decreased androgen levels in a time- and concentration-dependent fashion. This inhibitory effect correlated with a decrease in mRNA levels of Cyp17a1, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 h, GGPP alone and FPP alone had no effect on Cyp17a1 mRNA expression; however, the inhibitory action of simvastatin was partly abrogated by both GGPP and FPP. The present findings indicate that statin-induced reduction of androgen levels is likely due, at least in part, to the inhibition of isoprenylation, resulting in decreased expression of CYP17A1.

KW - Androgens/androgen receptor

KW - Cell culture

KW - CYP17A1

KW - Ovarian theca-interstitial cells

KW - Ovary

KW - Simvastatin

KW - Steroid hormones/steroid hormone receptors

KW - Steroidogenesis

KW - Theca cells

UR - http://www.scopus.com/inward/record.url?scp=84856863673&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856863673&partnerID=8YFLogxK

U2 - 10.1095/biolreprod.111.094714

DO - 10.1095/biolreprod.111.094714

M3 - Article

C2 - 21918126

AN - SCOPUS:84856863673

VL - 86

JO - Biology of Reproduction

JF - Biology of Reproduction

SN - 0006-3363

IS - 1

M1 - 20

ER -