UBC Theses and Dissertations
Interactive influence of apolipoprotein e genotype and dietary cholesterol on cholesterol synthesis in humans Main , Blair F.
Apolipoprotein (apo) E is a 299 amino acid polypeptide that mediates the uptake of apo E containing lipoproteins by receptor-mediated endocytosis. Allelic differences at the apo E gene locus are responsible for as much as 8% of the variance of low density lipoprotein (LDL) cholesterol. Due to the association between LDL cholesterol levels and atherosclerosis, it has been suggested that apo E polymorphism may play a role in determining the risk of coronary artery disease. A method for apo E genotyping was developed using the polymerase chain reaction (PCR) with allele-specific oligonucleotide primers. The fourteen phenotypes identified by isoelectric focusing methods were consistent with the fourteen genotypes identified by the PCR method. Seven E2/- and six E4/- volunteers were selected for a dietary study investigating the interactive effects of apo E polymorphism and dietary cholesterol levels on cholesterol synthesis rates. Volunteers underwent two dietary treatments consisting of a low cholesterol diet (250 mg/day) and a high cholesterol diet (800 mg/day). At the end of each diet period an oral dose of deuterium was given at 0.7 g/Kg body water to determine fractional synthetic rate (FSR) of cholesterol. The apo E4/- group had a significantly higher serum total cholesterol level than the E2/- group throughout both dietary treatments. Cholesterol FSR was not significantly different between apo E groups when comparing dietary cholesterol levels. The apo E4/- did respond to fasting state differently from the E2/- group by not depressing cholesterol synthesis while on a low cholesterol diet. This suggests E4/- individuals may not have a sensitive endogenous feedback mechanism to suppress cholesterol synthesis while on a low cholesterol diet.