Response of cholesterol synthesis to cholesterol feeding in men with different apolipoprotein E genotypes

To investigate the influence of dietary cholesterol level and apolipoprotein (apo) E polymorphism on cholesterol synthesis, seven apo E2/- and six apo E4/- normolipidemic subjects consumed self-selected diets containing low cholesterol ([LC] 250 mg/d) and high cholesterol ([HC] 800 mg/d) levels for approximately 20 days. On day 20, subjects were given 0.7 g deuterium oxide (D2O)/kg body water followed by maintenance doses. Cholesterol synthesis was measured as the uptake rate of D into plasma free cholesterol over 24 hours. Serum total cholesterol levels were higher (P < .05) in the apo E4/- versus apo E2/- group over both dietary periods. No influence of dietary cholesterol content on serum levels was observed, nor was there an effect of apo E genotype or dietary cholesterol level on cholesterogenesis. However, a genotype-independent association was observed between both cholesterogenesis (P < .001) and the increase in cholesterogenesis (P = .05) with the change in serum total cholesterol level subsequent to high-cholesterol feeding. These findings suggest that (1) apo E genotype is not associated with cholesterol synthesis rate in subjects on self-selected diets, and (2) hyporesponders to a dietary cholesterol challenge display higher synthetic rates than hyperresponders. The observation of lower cholesterol synthesis in individuals with the largest increases in serum cholesterol level after a dietary cholesterol challenge suggests a passive rather than dominant role of cholesterol synthesis in regulating serum levels.