Effect of human apolipoprotein E phenotype on endogenous cholesterol synthesis as measured by deuterium in corporation

Apolipoprotein (apo) E polymorphism may influence an individual's risk of developing ischemic heart disease through its effect on plasma cholesterol levels. Compared to individuals homozygous for the ε-3 allele (E3/3 phenotype), presence of the ε-2 allele (E2/2 or E3/2 phenotype) leads to lower, and the ε-4 allele (E4/4 or E4/3 phenotype) to higher, plasma cholesterol levels. The mechanisms responsible for these differences have not been completely identified, but are thought to be a result of the different binding properties of the apo E isoproteins. The purpose of this research project was to determine whether the rate of endogenous cholesterol production in healthy normolipidemic males is related to apo E phenotype. The study was of seven days duration. Subjects were selected from a group of 113 volunteers who were screened for apo E phenotype and plasma cholesterol and triglyceride levels. Subjects (E2/(2 or 3) group = 9, E4/(4 or 3) group = 9) consumed a standardized Western diet for five days and fasted on Day 6. Subjects drank 0.7 g deuterium oxide (D₂O)/kg body water at 0700 hr on Day 5, followed by dilute deuterium labelled drinking water to maintain constant enrichment levels on Days 5 and 6. The fractional synthetic rate (FSR) of cholesterol was determined over four consecutive 12-hour intervals on Days 5 and 6 by measurement of the incorporation of the stable isotope-labelled precursor, D₂O, from body water into free plasma cholesterol. Deuterium enrichment of plasma cholesterol and plasma water was determined by isotope ratio mass spectrometry. E2/- subjects had significantly lower (mean ± SEM) cholesterol FSR (0.070 ± 0.002/day) than E4/- subjects (0.097 ± 0.002/day) during the feeding period (p < 0.05). Cholesterol FSR was significantly reduced in all subjects during the fasting period (p < 0.001), although there were no differences between phenotype groups (E2/- = -0.002 ± 0.001/day; E4/- = 0.003 ± 0.001/day). Mean nocturnal cholesterol FSR following both the feeding and fasting periods was greater than daytime FSR (p < 0.05). These findings suggest that regulation of endogenous cholesterol synthesis may contribute to plasma cholesterol variations in men with different apo E phenotypes.Land and Food Systems, Faculty ofGraduat