Sensitivity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase to external stimuli and its relationship to in vivo rates of cholesterol synthesis in the fetal rat

Neil Christian Haave
During gestation the fetus requires cholesterol for membrane accretion, steroidogenesis and lipoprotein synthesis. Very little is known, however, about the mechanisms which regulate cholesterol synthesis in the fetus. When the bile-acid binding resin cholestyramine (CY) is fed to rats throughout gestation the activity of fetal hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (EC, rate-limiting enzyme of cholesterol synthesis in adult rats) increases. CY is not absorbed
more » ... CY is not absorbed from the gut into the circulation and therefore cannot cross the placenta. Hence, maternal CY feeding must alter fetal HMG CoA reductase activity by influencing maternal factors which are able to cross the placenta. The mechanism(s) mediating this increase in fetal hepatic HMG CoA reductase activity and whether this increase indicates an increase in hepatic cholesterol synthesis have not been previously studied. Thus, the objectives of this thesis are: (1) to determine if fetal hepatic HMG CoA reductase activity can be altered by changes in circulating hormones, cholesterol or fatty acids, and (2) to determine if changes in the activity of hepatic HMG CoA reductase can be correlated to changes in the rate of hepatic cholesterol synthesis in the near term rat. Experiments investigating the first objective demonstrated that fetal hepatic HMG CoA reductase activity cannot be altered through changes in maternal cholesterol or glucocorticoid levels and does not appear to be related to the concentration of insulin or thyroid hormone in fetal plasma. The quantity and/or type of fatty acid delivered to the fetus, however, appears to be a powerful determinant of fetal reductase activity. Maternal CY ingestion resulted in an increase in both the active (unphosphorylated) and total activity of fetal HMG CoA reductase. Maternal lipase activities and fetal hepatic fatty acid composition of rats fed CY suggest that altered delivery of fatty acids to the fetus may mediate changes in fetal hepatic HMG CoA reductase activity. Feeding pre [...]
doi:10.14288/1.0100396 fatcat:medbnk5frfa4hhunwrjnrjmwgu