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

• Main Author: Haave, Neil Christian
• Language: English
• Published: University of British Columbia 2011
• Online Access: http://hdl.handle.net/2429/31011

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 1.1.1.34, rate-limiting enzyme of cholesterol synthesis in adult rats) increases. 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 pregnant rats diets containing different amounts or types of fat produced fetal reductase activities that were more than two fold greater with 20% polyunsaturated (safflower oil) or monounsaturated (olive oil) fat diets then with the 20% saturated (palm oil) or 5% (safflower) fat diets. Thus, the quantity and/or type of fatty acid delivered to the fetus appears to be able to influence fetal hepatic HMG CoA reductase activity. Experiments studying the second objective demonstrated that, in contrast to adults, HMG CoA reductase activity is not correlated to in vivo rates of cholesterol synthesis in near term rat liver. Increased fetal hepatic reductase activity with CY or 20% fat feeding was not accompanied by increased rates of [³H]water incorporation into digitonin precipitable sterols in fetal rat liver during late gestation. In addition, hepatic reductase activity was found to increase during late gestation and to remain high until suckling commenced whereas rates of cholesterol synthesis peaked on gestation day 20 and then decreased, one day before birth. Thus, under the conditions studied, HMG CoA reductase activity did not indicate the in vivo rate of cholesterol synthesis in the near term rat liver. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate