In previous investigations, we have established that fresh human fetal liver tissue synthesizes cholesterol at high rates. Previous estimates of the amount of cholesterol in the fetus derived from the maternal compartment are in the range of 20%. Thus human fetal liver may be the principal source of circulating lipoprotein in the human fetus and since low density lipoprotein (LDL) is a major source of cholesterol regulating fetal adrenal steroid secretion, factors regulating cholesterol synthesis in the human fetal liver may indirectly control the rate of steroid secretion by the fetal adrenal cortex. The objective of the proposed research is to define the mechanisms that serve to regulate the rate of cholesterol biosynthesis and also the the binding, uptake, and catabolism of lipoproteins in the human fetal liver. In order to approach this objective human fetal liver membrane fractions or fetal liver cells maintained in monolayer culture will be utilized. The effects of steroids, peptides and thyroid hormones and growth factors on the rate of cholesterol synthesis will be determined by estimating the rate of incorporation of tritium from tritiated water into cholesterol and the specific activity of HMG CoA reductase. Other factors which may regulate the level of cholesterol in fetal plasma include its rate of removal by hepatic and other extra-hepatic tissues. Thus the number of lipoprotein receptors in fetal liver and the rate of lipoprotein metabolism by this tissue may serve to regulate in part the level of cholesterol in fetal plasma. It will be determined if the maximal specific binding capacity for lipoproteins of liver membrane fractions varies with gestational age and if steroids, peptides, thyroid hormones, growth factors and lipoproteins affect lipoprotein binding in fetal liver membrane preparations or the metabolism of lipoproteins in cultured fetal hepatocytes. These studies will provide considerable insight into the regulation of cholesterol synthesis, turnover of lipoprotein receptors and metabolism of lipoproteins in human fetal liver. This knowledge is crucial to our understanding of the hormonal regulation of fetal growth and maturation and possibly of the initiation of parturition. These studies may also provide additional infomation pertinent to the understanding and treatment of disorders of hyperlipemia and atherosclerosis.
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