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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034089-04
Application #
2889259
Study Section
Metabolism Study Section (MET)
Program Officer
Grave, Gilman D
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Rebholz, Sandra L; Jones, Thomas; Burke, Katie T et al. (2012) Multiparity leads to obesity and inflammation in mothers and obesity in male offspring. Am J Physiol Endocrinol Metab 302:E449-57
Rebholz, Sandra L; Burke, Katie T; Yang, Qing et al. (2011) Dietary fat impacts fetal growth and metabolism: uptake of chylomicron remnant core lipids by the placenta. Am J Physiol Endocrinol Metab 301:E416-25
Woollett, L A (2011) Review: Transport of maternal cholesterol to the fetal circulation. Placenta 32 Suppl 2:S218-21
Jones, Helen N; Woollett, Laura A; Barbour, Nicolette et al. (2009) High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J 23:271-8
Burke, Katie T; Colvin, Perry L; Myatt, Leslie et al. (2009) Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the golden Syrian hamster. J Lipid Res 50:1146-55
Yao, Lihang; Horn, Paul S; Heubi, James E et al. (2007) The liver plays a key role in whole body sterol accretion of the neonatal Golden Syrian hamster. Biochim Biophys Acta 1771:550-7
Yao, Lihang; Woollett, Laura A (2005) Adult sterol metabolism is not affected by a positive sterol balance in the neonatal Golden Syrian hamster. Am J Physiol Regul Integr Comp Physiol 288:R561-6
Woollett, Laura A (2005) Maternal cholesterol in fetal development: transport of cholesterol from the maternal to the fetal circulation. Am J Clin Nutr 82:1155-61
Hayden Lichtenberg, M; Wilke, Catherine S; McConihay, Julie A et al. (2005) Yolk sac cholesteryl ester secretion rates can be manipulated in the Golden Syrian hamster: effect of yolk sac cholesterol concentrations. Biochim Biophys Acta 1735:214-21
Schmid, Kara E; Davidson, W Sean; Myatt, Leslie et al. (2003) Transport of cholesterol across a BeWo cell monolayer: implications for net transport of sterol from maternal to fetal circulation. J Lipid Res 44:1909-18

Showing the most recent 10 out of 15 publications