Considerable insight into the roles of lipoproteins ( and apoproteins) in normal subjects and patients with dyslipoproteinemias can be gained by evaluating individuals with specific inborn errors of lipoprotein metabolism. This proposal request support for continued nutritional and metabolic investigations in patients with phenotypic abetalipoproteinemia (ABL). To examine whether or not the nocturnal increase in plasma concentrations of mevalonic acid ( which parallel an increase in cholesterol biosynthesis) seen in normal subjects reflects a lack of hepatic uptake of chylomicron remnants, we propose to examine nutritional and hormonal influences on the concentrations of the mevalonic acid in the plasma of patients with ABL as compared to control subjects and a patient with normotriglyceridemic ABL. Studies in patients with ABL will examine the metabolic turnover of the apoprotein E and apoprotein A1 moieties of HDL, determine whether or not immunologically detectable apoprotein B is present in the intestinal mucosa of a patient with homozygous HBL and determine whether our previously demonstrated impaired adrenal response to ACTH stimulation in ABL can be corrected by an infusion of LDL. We have recently demonstrated reduced plasma progesterone during pregnancy in a patient with homozygous HBL and the biological capability to maintain pregnancy. We propose to examine whether the placenta of this patient increases cholesterol biosynthesis and LDL receptor activity in an attempt to compensate for the lack of maternal LDL and the ability of lipoproteins present in the plasma of patients with ABL to supply cholesterol for progesterone biosynthesis. Human milk triglycerides are believed to be derived from the fatty acids present in triglyceride-rich lipoproteins and studies on the lipid composition of breast milk will be conducted to determine how this is influenced by the inherent absence of chylomicrons and whether the predicted abnormal fatty acid composition can be modified by the intravascular infusion of an exogenous triglyceride emulsion (Intralipid). Vitamin E absorption and transport is abnormal in ABL. We plan to examine where vitamin E is carried in ABL plasma and whether or not their HDL particles can function to deliver vitamin E to cells in a manner analagous to the way LDL is believed to function in normal subjects. Finally, collaborative studies have been initiated to examine the molecular defect in ABL now that the gene for apolipoprotein B has been cloned.
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