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Regulation of Pathways Determining Cholesterol Availability in the Baboon Placenta with Advancing Gestation¹

^a Departments of Obstetrics/Gynecology, ^b Physiology, ^c Anatomy, and ^d the Interdisciplinary Program in Molecularand Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112 ^e Tulane Regional Primate Research Center,Covington, Louisiana 70433 ^f Department of Medicine, University of California-San Francisco, and Veterans Affairs Medical Center, San Francisco, California 94121

Low density lipoprotein (LDL) is accepted as the primary source of cholesterol for progesterone biosynthesis in the primate placental syncytiotrophoblast. We hypothesized that the syncytiotrophoblast may, however, derive significant amounts of cholesterol from sources in addition to the LDL pathway, especially during early pregnancy or when faced with a paucity of lipoprotein-cholesterol. To test this, alternate cholesterol-providing pathways were assessed in placentae at early (Days 60–61), mid (Days 98–102), and late (Days 160–167) gestation in the baboon (Papio sp., term ~184 days). Expression of LDL receptor mRNA transcripts in an enriched fraction of syncytiotrophoblast cells was approximately 13-fold greater (P < 0.05) in mid and late gestation than in early pregnancy, although no differences were observed in whole villous tissue. The abundance of transcripts for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme responsible for de novo cholesterol synthesis, remained unchanged in syncytiotrophoblast cells; however, HMG-CoA reductase activity declined approximately 2-fold from early to late pregnancy (P < 0.01), with a commensurate decline in immunoreactive HMG-CoA reductase protein. Activities for acyl-coenzyme A:cholesterol acyl transferase (ACAT), a rate-limiting enzyme for cholesterol esterification, were greater (P < 0.05) at early and mid pregnancy in placental homogenates than in those from late pregnancy, while ACAT-1 mRNA concentrations 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 progesterone production during early baboon pregnancy, its contribution declines with advancing gestational age as LDL receptor-derived cholesterol becomes the major source of substrate. Changes in LDL receptor mRNA abundance suggest differences in mechanisms regulating cholesterol homeostasis in steroidogenically active syncytiotrophoblasts vs. proliferative nonendocrine cell types in the placenta.

¹ This work was supported by NIH Research Grants R29 HD32502 (M.C.H.), HL52069 (S.K.E.), a Merit Award from the Department of Veterans Affairs (S.K.E.), and by P51 RR00164–35 (Tulane Regional Primate Research Center). It was presented in part at the 80th Annual Meeting of The Endocrine Society.

² Correspondence: Michael C. Henson, Department of Obstetrics/Gynecology, Tulane University School of Medicine, 1430 Tulane Avenue, Room 4500, New Orleans, LA 70112-2699. FAX: 504 584 1846; michael.henson{at}tulane.edu

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