ENDOGENOUS AND EXOGENOUS SOURCES OF CHOLESTEROL DURING FETAL DEVELOPMENT
Cholesterol is essential for proper fetal development. Defects in fetal cholesterol metabolism can cause developmental abnormalities, including mental retardation and stunted growth as demonstrated by patients with Smith-Lemli-Optiz syndrome. Understanding fetal cholesterol metabolism could lead to the development of a method to prevent or lessen cholesterol deficiency related birth defects. Therefore, the goal of this dissertation was to examine cholesterol metabolism in the developing fetus. Understanding cholesterol metabolism requires the examination of both sources of cholesterol: cholesterol synthesized de novo and cholesterol provided exogenously. De novo cholesterol synthesis in the adult can be regulated by dietary polyunsaturated fatty acids. If fetal cholesterol synthesis rates are regulated as in the adult, then the consumption of polyunsaturated fatty acids during pregnancy may have an impact on fetal development. Therefore, the regulation of cholesterol synthesis in the fetus was examined. Pregnant hamsters were fed various fatty acids throughout gestation and sterol synthesis rates in the fetus were determined. Although the rate of sterol synthesis in the adult hamster was decreased by dietary polyunsaturated fatty acids, sterol synthesis rates in the fetus were unaffected. In addition, the adult could be made to become unresponsive to dietary polyunsaturated fatty acids by inducing a negative sterol balance across the liver. These data demonstrated that sterol synthesis is regulated differently in fetal tissues as compared to adults, possibly due to a negative sterol balance in the fetus. The placenta regulates the transport of exogenous nutrients from the maternal circulation to the fetal circulation. The placental transport of glucose and fatty acids is well established, however the transport of cholesterol remains undefined. Therefore, a human choriocarcinoma cell line, BeWo, was utilized to model the transport of cholesterol across a placental monolayer. It was demonstrated that cholesterol could be transported from the apical surface of the placental cell to the basolateral surface for efflux to components of fetal human serum, fetal HDL and phospholipid vesicles but not apolipoprotein A-I. BeWo cells demonstrated a mass movement of cholesterol from the apical to basolateral chamber that could be manipulated by increasing the cellular cholesterol concentration. These were the first studies to utilize an in vitro model to demonstrate the transport of cholesterol from the maternal circulation (apical side) to the fetal circulation (basolateral side). Understanding and dissecting this pathway may aid in the development of in utero treatments for fetuses with defects in cholesterol biosynthesis.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:fetal cholesterol metabolism placental transport synthesis smith lemli optiz
Date of Publication:01/01/2003