Regulation of cholesterol intake by the corpus luteum

Abstract  Ovarian cholesterol supply is rate limiting to ovarian steroidogenesis.  For this reason, the majority of cholesterol required for steroid synthesis is imported via scavenger receptor-BI (SR-BI) and the low-density lipoprotein (LDL) receptor from circulating HDL and LDL. SR-BI mRNA is expressed in pig ovaries at all stages of folliculogenesis and in the corpus luteum (CL). SR-BI protein expression in mouse ovary during estrous cycle was also detected. In both species, expression is concentrated in cytoplasm and periphery of follicular cells.  Gonadotropins induce SR-BI expression in pig granulosa cells, with cytoplasmic expression increasing through the periovulatory period, with migration to the cell periphery as the CL matured.  An 82-kDa form of SR-BI is strongly expressed in the pig CL, with the less abundant 57-kDa form,  differences between forms are attributable to glycosylation.  In vitro culture of pig follicles with human chorionic gonadotropin (hCG) induced time-dependent upregulation of 82-kDa SR-BI in granulosa cells. SR-BI and LDL receptor were reciprocally expressed, with the latter highest in follicular granulosa cells, declining precipitously with CL formation.  To further explore mechanisms of cholesterol supply to ovarian steroidogenesis, we examined mice treated to uncouple ovulation and mice bearing null mutation of the Scarb1 gene (SR-BI-/-). Results show entrapped oocytes in luteinized structures expressed SR-BI.  SR-BI-/- mice displayed small corpora lutea, large follicles with theca cells hypertrophied, follicular cysts with blood filled cavities and 50% decreased in plasma progesterone. In SR-BI-/- mice, treatment with a combination of 20 g/g of mevinolin and 100 g/g of chloroquine (CHLORO) was employed to disturbed cholesterol sources.  Serum progesterone was reduced by 43% in wild type and 30% in SR-BI-/- mice.  The protein expression of the rate-limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) increased in SR-BI-/- mice.  It was concluded that follicular cells express SR-BI during follicle development and luteinization causes upregulation of SR-BI expression.  Posttranslational maturation is characterized by glycosylation.  Under normal conditions expression of the LDLr (low density lipoprotein recepors) is extinguished during luteinization such that SR-BI becomes the principal means of importation of extracellular cholesterol. Further, perturbation of cholesterol de novo synthesis and uptake from LDLr in SR-BI-/- mice leads to a reduction of luteal function.  Ovarian cholesterol homeostasis is central to adequate luteinization, and its perturbation leads to reduction, but not to complete impairment, of luteal function.  We conclude that SR-BI expression is an important but not essential factor in maintaining ovarian cholesterol homeostasis, steroid synthesis and luteinization. A network of complementary and compensatory cholesterol supply mechanisms act in concert to assure ovarian steroid synthesis.

Keyphrases: Ovary, Follicle, Corpus luteum, Cholesterol, Cholésterol, SR-BI, SR-BI, Lipoprotein receptors