The Orphan Nuclear Receptor, Liver Receptor Homolog-1, Regulates Cholesterol Side-Chain Cleavage Cytochrome P450 Enzyme in Human Granulosa Cells

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.

The small heterodimer partner is a gonadal gatekeeper of sexual maturation in male mice

“…Steroidogenic genes have been shown to be regulated by both SF-1 and LRH-1 in vitro (Bakke et al 2001;Kim et al 2004Kim et al , 2005Mueller et al 2006). In agreement with a previous report (Pezzi et al 2004), we confirmed that the mRNA of lrh-1 was clearly expressed in the interstitial cells (Fig.…”

“…LRH-1 and SF-1 recognize the same DNA-binding sites and have been shown to control the expression of many steroidogenic genes (Bakke et al 2001;Kim et al 2004Kim et al , 2005Mueller et al 2006). As SHP was known to repress LRH-1, and both NRs are coexpressed in interstitial cells, we hypothesized that LRH-1 might regulate testicular steroidogenesis.…”

“…The two members of the NR5A subfamily of NRs-the steroidogenic factor 1 (SF-1, NR5A1) and the liver receptor homolog 1 (LRH-1, NR5A2)-have been shown to control the transcription of many genes involved in steroidogenesis (Bakke et al 2001;Kim et al 2004Kim et al , 2005Mueller et al 2006). While deletion of SF-1 in the steroidogenic Leydig cells results in infertility in male mice primarily driven by an abnormal testicular descent (Jeyasuria et al 2004), the role of LRH-1 in the Leydig cells of the testis remains elusive (Pezzi et al 2004).…”

Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1

“…Both factors thus commonly regulate the transcription of the same genes. This phenomenon is also applicable to steroidogenesis-related genes, including cytochrome P450 steroid hydroxylases (Kim et al, 2005;Pezzi et al, 2004;Wang et al, 2001;Yazawa et al, 2009;Yazawa et al, 2010;Yazawa et al, 2011), cholesterol deliverers (Kim et al, 2004;Schoonjans et al, 2002), hydroxysteroid dehydrogenase (Peng et al, 2003) and electron transporter (Table 1). Thus, in addition to SF-1, it is conceivable that LRH-1 also works as a determining factor in cell-specific expression of steroidogenesis-related genes.…”

Intestinal Epithelium–Specific Knockout of the Cytochrome P450 Reductase Gene Exacerbates Dextran Sulfate Sodium–Induced Colitis

“…Previous studies have shown that the protein LRH-1 (liver homologue-1) is a potent regulator of some of these CYP genes in the adrenal glands and ovaries (Fayard et al, 2004;Kim et al, 2005), as well as in the intestine (Mueller et al, 2006). LRH-1 expression is induced upon immune stimulation, coincident with the induction of CYP11A1 and CYP11B1.…”