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The Role of the Orphan Nuclear Receptor, Liver Receptor Homologue-1, in the Regulation of Human Corpus Luteum 3ß-Hydroxysteroid Dehydrogenase Type II

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas Texas 75390-9032

Address all correspondence and requests for reprints to: George R. Attia, M.D., Department of Obstetrics and Gynecology, University of Miami, 7007 Holtz Center, JMH East Tower, 1611 NW 12th Avenue, Miami, Florida 33136. E-mail: gattia{at}med.miami.edu.

After ovulation, ovarian 3ß-hydroxysteroid dehydrogenase type II (HSD3B2) expression increases to enhance the shift of steroidogenesis toward progesterone biosynthesis. Steroidogenic factor-1 (SF-1) is a transcription factor for several genes encoding steroidogenic enzymes. However, the level of SF-1 expression decreases in the human corpus luteum (CL) after ovulation. Liver receptor homolog-1 (LRH-1) is another member of the orphan nuclear receptor family. We hypothesize that LRH-1, rather than SF-1, plays an essential role in the regulation of corpus luteum steroidogenesis. Semiquantitative RT-PCR and real-time PCR were performed to quantify the level of LRH-1 expression and correlate with HSD3B2 level. Cell transfection, mutation analysis, and EMSA were performed to examine the role of LRH-1 in the regulation of HSD3B2. LRH-1 expression was higher in CL, compared with mature ovarian follicles. Cotransfection of granulosa cells with HSD3B2 and LRH-1 resulted in a 10-fold increase of transcription. DAX-1 inhibited LRH-1-stimulated HSD3B2, which was maintained in the presence of dibutyryl cAMP. Mutation of the either of the two putative LRH-1 binding sites, which were confirmed by EMSA, in the HSD3B2 promoter decreased LRH-1 stimulation. Our findings suggest that LRH-1 is highly expressed in CL, and it plays an essential role in the regulation of HSD3B2.

Abbreviations: DAX-1, Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1; dbcAMP, dibutyryl cAMP; DME/F12, DMEM and Ham’s F-12 medium; FP, free probe; GCT, granulosa cell tumor; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; HLGC, human luteinized granulosa cell; HSD3B2, 3ß-hydroxysteroid dehydrogenase type II; IVP, in vitro protein; LRH-1, liver receptor homologue-1; NE, nuclear extract; PKA, protein kinase A; RT, reverse transcription; SF-1, steroidogenic factor-1.

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