Regulation of pathways determining cholesterol availability in the baboon placenta with advancing gestation

Low density lipoprotein (LDL) is accepted as the primary source of choleste rol for progesterone biosynthesis in the primate placental syncytiotrophobl ast. We hypothesized that the syncytiotrophoblast may, however, derive sign ificant amounts of cholesterol from sources in addition to the LDL pathway, especially during early pregnancy or when faced with a paucity of lipoprot ein-cholesterol. To test this, alternate cholesterol-providing pathways wer e assessed in placentae at early (Days 60-61), mid (Days 98-102), and late (Days 160-167) gestation in the baboon (Papio sp., term similar to 184 days ). Expression of LDL receptor mRNA transcripts in an enriched fraction of s yncytiotrophoblast cells was approximately 13-fold greater (P < 0.05) in mi d and late gestation than in early pregnancy, although no differences were observed in whole villous tissue. The abundance of trans scripts for 3-hydr oxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme responsible for de novo cholesterol synthesis, remained unchanged in syncytiotrophobla st cells; however, HMG-CoA reductase activity declined approximately 2-fold from early to late pregnancy (P < 0.01), with a commensurate decline in im munoreactive HMG-CoA reductase protein. Activities for acyl-coenzyme A:chol esterol acyl transferase (ACAT), a rate-limiting enzyme for cholesterol est erification, were greater (P < 0.05) at early and mid pregnancy in placenta l homogenates than in those from late pregnancy, while ACAT-1 mRNA concentr ations and cholesterol ester hydrolase activity remained unchanged. These results, taken together, suggest that although de novo synthesis has the potential to provide a measure of the cholesterol used for placental pr ogesterone production during early baboon pregnancy, its contribution decli nes with advancing gestational age as LDL receptor-derived cholesterol beco mes the major source of substrate. Changes in LDL receptor mRNA abundance s uggest differences in mechanisms regulating cholesterol homeostasis in ster oidogenically active syncytiotrophoblasts vs. proliferative nonendocrine ce ll types in the placenta.