The effect of dietary manipulation on fetal and maternal cholesterol metabolism in the guinea pig.

Abstract

Diets consisting of non-purified guinea pig diet or non-purified guinea pig diet supplemented with either 1.1% of the bile acid binding resin cholestyramine or 0.25% cholesterol were fed to dams from the first day of conception. Whole body rates of endogenous cholesterol synthesis and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA levels were determined at 0, 40 and 60 days of gestation in the dam and fetus. Sterol synthesis studies indicated that maternal hepatic cholesterol synthesis was reduced 87% by dietary cholesterol and was increased 2.9-fold with cholestyramine feeding. The pattern of fetal hepatic and peripheral tissue cholesterol synthesis rates during development indicated that synthesis was highest at 40 days gestation, and by 60 days was reduced to levels similar to that found in the adult. Cholesterol synthesis rates in the fetus were relatively insensitive to dietary manipulation; however, maternal cholestyramine treatment did result in a 1.4-fold increase in fetal carcass cholesterol synthesis at 60 days gestation. To determine whether regulation at the level of feedback suppression or induction of steady state RNA levels were also present in the fetal organism, mRNA levels for HMG-CoA reductase were quantified in the maternal and fetal liver. In these studies the guinea pig was shown to have two reductase mRNA species of 4.5 and 3.2 kb, similar to transcript sizes identified for the hamster, rat and Drosophila. Although nearly equimolar in the 40 day gestation fetus the 3.2 kb transcript predominated at 60 days. Dietary treatment had only minor effects on fetal reductase mRNA levels at 40 days gestation; however, at 60 days gestation, fetuses from cholestyramine-fed dams had elevated levels of reductase mRNA and fetuses from cholesterol fed dams had reduced levels of reductase mRNA. These studies indicate that maternal cholesterogenic systems maintain responsiveness to dietary regulation during pregnancy at both the level of sterol synthesis rates and HMG-CoA reductase mRNA levels. These findings also indicate that it is possible to influence those mechanisms which modulate cholesterol homeostasis prenatally. Further studies will be required to determine if such effects extend into the post-natal period and beyond.