Mevalonate metabolism in pregnant rats

Abstract

Mevalonate is converted to cholesterol by the sterol pathway or can be oxidized to CO 2 by the shunt pathway; the kidneys are the chief site of mevalonate metabolism in both pathways. Recently, a major sex difference in circulating mevalonate metabolism has been observed in rats and in humans; in rats, females oxidized mevalonate to CO 2 at twice the rate of the males, but males converted mevalonate to cholesterol to a greater extent than did females. Sex hormones are believed to mediate these sex differences in mevalonate metabolism. In rats and humans, the hypercholesterolemia associated with pregnancy begins in the second trimester and reaches a maximum at term. The present study was undertaken to determine if alterations in the metabolism of circulating mevalonate occur during pregnancy. In 12-day pregnant animals, the metabolism of circulating mevalonate by the shunt pathway was increased (116 nmole mevalonate converted to CO 2 versus 94.6 nmole in control animals), whereas in the 18-day pregnant animals the shunt pathway was decreased below control values (72.9 nmole). Associated with this decrease in circulating mevalonate metabolism by the shunt pathway in the 18-day pregnant animals was an increase in the synthesis of nonsaponifiable lipids in the liver (26.8 versus 21.5 nmole of mevalonate incorporated). These changes correlated with the period of maximal hypercholesterolemia in pregnant rats. The increase in circulating mevalonate metabolism by the shunt pathway in 12-day pregnant animals was accompanied by a decrease in total body nonsaponifiable lipid synthesis (259.3 nmole of mevalonate converted by controls versus 235.1 nmole by 12-day pregnant rats). Renal sterol synthesis from circulating mevalonate was unaffected by pregnancy. The fetuses and placentas of the 12-day and 18-day pregnant animals converted circulating mevalonate to nonsaponifiable lipids, primarily cholesterol, indicating that maternal circulating mevalonate serves as a source of cholesterol for the fetus and the placenta. This study demonstrates that the metabolism of circulating mevalonate is influenced by pregnancy and that circulating maternal mevalonate is a precursor of fetal and placental cholesterol.