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Lipoprotein Enhancement of Ovarian Theca-Interstitial Cell Steroidogenesis: Relative Contribution of Scavenger Receptor Class B (Type I) and Adenosine 5'-Triphosphate- Binding Cassette (Type A1) Transporter in High-Density Lipoprotein-Cholesterol Transport and Androgen Synthesis

Departments of Obstetrics/Gynecology and Biological Chemistry (Q.W., K.M.J.M.), University of Michigan Medical School, Ann Arbor, Michigan 48109; and Geriatric Research, Education and Clinical Center (S.S., S.A.), VA Palo Alto Health Care System, Palo Alto, California 94304

Address all correspondence and requests for reprints to: K. M. J. Menon, University of Michigan Medical School, 6428 Medical Sciences Building I, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0617. E-mail: kmjmenon{at}med.umich.edu.

The theca-interstitial cells take up plasma high-density lipoprotein (HDL)- and low-density-lipoprotein-derived cholesterol to convert into steroid hormones. The uptake of HDL-derived cholesterol is mediated by the scavenger receptor, class B, type I (SR-BI). In nonsteroidogenic cells, HDL-stimulated efflux of cholesterol has been shown to be mediated by the ATP-binding cassette A1 (ABCA1) transporter. Its expression has not been documented in steroidogenic cells. The goal of the present study was to determine: 1) the role of SR-BI in theca-interstitial cell androgen production; 2) whether theca-interstitial cells express ABCA1 transporter mRNA; and 3) the relative roles of SR-BI and ABCA1 transporter in androgen production. The ABCA1 transporter mRNA expression in rat theca-interstitial cells was shown using RT-PCR and Northern blot analyses. The role of SR-BI and ABCA1 in androstenedione production was also examined by treating cells with anti-SR-BI and 2-hydroxypropyl-ß-cyclodextrin in the presence and absence of human chorionic gonadotropin and/or human HDL₃. The treatment of theca-interstitial cells with anti-SR-BI antibody blocked more than 90% of HDL plus human chorionic gonadotropin-stimulated androstenedione production, and selective HDL-CE uptake. On the other hand, the use of inhibitors of ABCA1 transporter function had no discernible effect on HDL-supported androgen production. These data demonstrate that, although theca-interstitial cells express both SR-BI and ABCA1 transporter mRNA, the SR-BI pathway supplies the majority of the cholesterol required for androgen production. Furthermore, the present study presents evidence for a crucial role for SR-BI in HDL-mediated androgen production.

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