Regulation of luteinizing hormone/chorionic gonadotropin receptor messenger ribonucleic acid expression in the rat ovary: relationship to cholesterol metabolism.

Abstract

Down-regulation of LH/human chorionic gonadotropin (hCG) receptor (LHR) mRNA in the ovary after the preovulatory LH surge or the administration of a pharmacological dose of LH/hCG occurs through a posttranscriptional mechanism. A LHR mRNA-binding protein was identified as the LHR mRNA destabilizing factor, and its identity was established as mevalonate kinase (Mvk). In the present study, we determined that, in the pseudopregnant rat ovary, LHR mRNA levels began to fall 4 h after hCG injection, at which time Mvk protein levels were elevated, and this elevation was preceded by an increase in Mvk mRNA levels. When the cytosolic fractions of hCG-treated ovaries were subjected to RNA EMSA, an increase in LHR mRNA-LHR mRNA-binding protein complex formation was observed, in parallel with the increase of Mvk expression. We also found that hCG coordinately up-regulated the expression of Mvk and other sterol-responsive elements containing cholesterol biosynthesis enzymes, such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and farnesyl pyrophosphate synthase. This up-regulation was transient, but the hCG-induced ovarian cholesterol depletion lasted for more than 24 h. Taken together, our results suggest that, in the ovary, LH/hCG up-regulates the expression of cholesterol biosynthesis enzymes and lipoprotein receptors to replenish cellular cholesterol, and the up-regulation of Mvk leads to a down-regulation of LHR and suppresses the LH/hCG signal cascade transiently. Thus Mvk, an enzyme involved in cholesterol biosynthesis, serves as a link between LHR mRNA expression and cellular cholesterol metabolism.