The acquisition of sterol by the fetus is essential for development and growth. Three potential sources of sterol for the fetus are de novo synthesis, cholesterol synthesized within other fetal tissues that is transported to the fetus and maternal lipoproteins. Without the required amount of cholesterol from these sources, the fetus will not survive or will develop abnormally. Thus, the overall aim of this proposal is to delineate the mechanisms by which the fetus and other fetal tissues, such as the placenta, yolk sac and decidua, derive the lipids needed for normal fetal development. In the first set of studies, the amount of fetal hamster cholesterol that originates from de novo synthesis, from synthesis within other fetal tissues and from the maternal circulation will be quantitated. In addition, lipoprotein-like particle formation in and secretion from the yolk sac, the process by which the fetus obtains exogenous cholesterol, will be manipulated and the compensatory mechanisms involved in maintaining fetal sterol metabolism will be evaluated: mice with low levels of apolipoprotein B (apoB) as compared to mice that overproduce apoB will be used for these experiments. In the second and third sets of studies, maternal low and high density lipoprotein-cholesterol concentrations (LDL-C and HDL-C, respectively) will be varied to mimic concentrations found in a typical Western population, and the effects these differences in concentrations have on fetal development will be evaluated in hamsters fed different diets and in mice with either normal or low apolipoprotein AI levels. Additionally, the pregnancy-induced hypercholesterolemia that normally occurs during the third trimester will be blocked in hamsters to examine how the fetal tissues compensate for a lack of maternal LDL-C. Finally, various fatty acids will be fed to pregnant hamsters and the resultant, effect they they have on sterol metabolism in the tissues of the fetus, including the brain, will be evaluated. These studies will be the first to determine how much fetal cholesterol is derived from the maternal circulation versus that originating in the other fetal tissues, and will begin to elucidate the cellular processes involved in the maintenance of sterol metabolism in the fetus in a population with different plasma LDL- and HDL-C concentrations.
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