The orphan nuclear receptor, liver receptor homolog-1, regulates cholesterol side-chain cleavage cytochrome P450 enzyme in human granulosa cells

Joung W. Kim, Jon C. Havelock, Bruce R. Carr, George Attia

Research output: Contribution to journalArticle

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Abstract

After ovulation, there is a shift in ovarian steroidogenesis from an estrogen-producing ovarian follicle to a progesterone-producing corpus luteum. The first step in human ovarian steroidogenesis is catalyzed by cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme. Steroidogenic factor-1 is an orphan nuclear receptor that regulates several steroidogenic enzymes, including CYP11A1. Liver receptor homolog-1 (LRH-1) is another orphan nuclear receptor that is expressed in the human ovary. After ovulation there is a down-regulation in steroidogenic factor-1, which is associated with an up-regulation of LRH-1 expression. These changes coincide with increased level of CYP11A1 expression in human corpus luteum. In this study, we examined the role of LRH-1 in the regulation of human granulosa cell CYP11A1 expression. Cotransfection of human granulosa cell tumor cells with CYP11A1 promoter and LRH-1 expression vector resulted in a significant increase in CYP11A1 expression. Deletion analysis revealed two putative LRH-1 binding sites at -1580 and -40, which was confirmed by EMSA. Dosage-sensitive sex-reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene-1 inhibited LRH-1 stimulated CYP11A1 expression, and that was not overcome by the presence of PKA agonist. We conclude that CYP11A1 expression in human granulosa cells is regulated by LRH-1. We propose that LRH-1 could be the major transcription factor for the post-ovulatory surge in human ovarian steroidogenesis.

Original languageEnglish
Pages (from-to)1678-1685
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number3
DOIs
StatePublished - Mar 1 2005

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Cholesterol Side-Chain Cleavage Enzyme
Orphan Nuclear Receptors
Granulosa Cells
Liver
Cytochrome P-450 Enzyme System
Cholesterol
Steroidogenic Factor 1
Corpus Luteum
Ovulation
Granulosa Cell Tumor
X-Linked Genes
Ovarian Follicle
Chromosomes, Human, Pair 1
Chromosomes
Progesterone
Tumors
Ovary
Estrogens
Transcription Factors
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

The orphan nuclear receptor, liver receptor homolog-1, regulates cholesterol side-chain cleavage cytochrome P450 enzyme in human granulosa cells. / Kim, Joung W.; Havelock, Jon C.; Carr, Bruce R.; Attia, George.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 3, 01.03.2005, p. 1678-1685.

Research output: Contribution to journalArticle

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