Effects of Reduced Maternal Lipoprotein-Cholesterol Availability on Placental Progesterone Biosynthesis in the Baboon

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Abstract
Maternal low density lipoprotein (LDL) is the principal source of cholesterol substrate for progesterone biosynthesis in the primate placental syncytiotrophoblast. The relationship of LDL-cholesterol availability and other potential cholesterol-yielding pathways to pla- cental progesterone production have not, however, been demon- strated in vivo in a nonhuman primate. Therefore, maternal periph- eral lipoprotein-cholesterol and progesterone concentrations were determined in blood samples obtained by venipuncture, from day 72 until day 100, from pregnant baboons (Papio sp) that were either untreated (n 5 4) or treated (n 5 3) with the inhibitor of hepatic lipoprotein production, 4-aminopyrazolo (3- 4-d)pyrimidine (4-APP, 10 mg/kg BW) on days 98 -99 of pregnancy (term 5 184 days). Al- though LDL-cholesterol and progesterone levels remained unchanged in untreated animals, LDL-cholesterol concentrations were 9-fold lower (P , 0.005) in baboons receiving 4-APP than in untreated baboons 2 days following initial administration. Commensurate pro- gesterone levels were 3.5-fold lower (P , 0.03) in 4-APP-treated ba- boons than in untreated baboons. RT-PCR was used to approximate relative changes in transcription of messengers RNAs (mRNAs) for selected cholesterol-sensitive pathways in placental tissue collected on day 100. Thus, expression of mRNAs for LDL receptor and 3-hy- droxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase appeared enhanced, whereas acyl-coenzyme A:cholesterol acyl transferase (ACAT) mRNA was diminished in syncytiotrophoblast-enriched cell fractions as a result of 4-APP administration. No relative differences in mRNAs were apparent in whole placental villous tissue, however, as a result of 4-APP treatment. In summary, this experiment demonstrates a significant decline in progesterone production elicited by maternal LDL-cholesterol with- drawal, and attests to the efficacy of 4-APP administration during baboon pregnancy. These results also suggest a commensurate reg- ulation of cholesterol-sensitive pathways in primate syncytiotropho- blast. However, no relative differences were apparent in mRNA levels for LDL receptor, HMG-CoA and ACAT in whole placental villous tissue as a result of LDL-cholesterol withdrawal, which may suggest potential disparities in the mechanisms regulating cholesterol ho- meostasis in steroidogenically active syncytiotrophoblasts vs. those in proliferative nonendocrine placental constituents. (Endocrinology 138: 1385-1391, 1997)

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