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Ribonucleic Acid Binding Protein-Mediated Regulation of Luteinizing Hormone Receptor Expression in Granulosa Cells: Relationship to Sterol Metabolism

Departments of Obstetrics and Gynecology and Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109

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

Posttranscriptional mechanism plays a crucial role in regulating LH receptor (LHR) expression in the ovary. We have identified a novel trans-factor, LHR mRNA binding protein (LRBP), which binds to a polypyrimidine-rich bipartite sequence of the coding region of LHR mRNA, and its identity was established as mevalonate kinase (Mvk). Although an inverse relation between LHR mRNA expression and RNA binding activity of LRBP has been established, its intermediary role in LHR mRNA expression has not been demonstrated. The present study examined the direct role of Mvk in regulating LHR expression by using primary cultures of human granulosa cells as a model system. A marked decrease in LHR mRNA stability and an increase in Mvk expression were seen when cultured granulosa cells were treated with human chorionic gonadotropin (hCG) in vitro. This treatment also resulted in an increase in LHR mRNA binding activity in the cytosolic fractions prepared from hCG-treated cells compared with the control. Because Mvk expression is regulated by sterol response element-binding protein-1, which is sensitive to the cellular concentration of 25-hydroxycholesterol (25-OHC), cultured granulosa cells were treated with this oxysterol, and the expression of Mvk gene was examined. As expected, treatment with 25-OHC inhibited the Mvk (LRBP) expression, as well as the LHR mRNA binding activity of LRBP. To determine the role of Mvk in ligand-mediated down-regulation of LHR mRNA, cells were additionally treated with 25-OHC when treated with hCG. The results showed that the decrease in Mvk expression by oxysterol treatment abrogated ligand-induced down-regulation of LHR mRNA. These results therefore establish a direct participation of Mvk in regulating LHR expression and suggest a novel relationship between cholesterol metabolism and LHR expression in the ovary.