Cholesterol Absorption and Metabolism and LDL Kinetics in Healthy Men With Different Apoprotein E Phenotypes and Apoprotein B Xba I and LDL Receptor Pvu II Genotypes

Abstract

Abstract Apoprotein (apo) E, apoB Xba I, and LDL receptor gene Pvu II polymorphisms are associated with LDL cholesterol level, but little is known about cholesterol and LDL metabolism in subjects with the latter two genetic polymorphisms alone or in combination with different apoE phenotypes. We studied cholesterol absorption efficiency, cholesterol and bile acid synthesis, and LDL apoB kinetics in 52 healthy men and related the metabolic results to the apoB Xba I and LDL receptor Pvu II restriction fragment length polymorphism (RFLP) and apoE phenotypes. New findings were as follows. ApoB Xba I polymorphism was not associated with the metabolic variables of cholesterol, but LDL receptor Pvu II RFLP was associated with fractional catabolic rate for LDL apoB, cholesterol absorption, and cholesterol and bile acid synthesis. ApoE polymorphism exerted the most powerful effect on the LDL cholesterol concentration, so that the apoE2 subjects had the lowest LDL cholesterol and apoB levels and cholesterol absorption, and the highest fractional catabolic rate and bile acid and cholesterol synthesis compared with the apoE3 or especially apoE4 phenotypes in different genetic combinations. In multiple stepwise regression analysis with LDL cholesterol as the dependent and the genetic and metabolic parameters as the independent variables, 47.0% (n=35, P <.001) of the variability of LDL cholesterol was explained by the apoE polymorphism, 7.1% ( P <.05) by the LDL receptor Pvu II RFLP, and 11.3% ( P <.01) by bile acid synthesis, while the contribution of the apoB Xba I RFLP was nonsignificant. In conclusion, LDL cholesterol level was lowest in subjects with the ε2 allele, irrespective of their Xba I or Pvu II genotypes; this was due to lower cholesterol absorption efficiency, more effective cholesterol and bile acid synthesis, and more efficient fractional catabolic rate in carriers of the ε2 allele when compared with the other genetic subgroups.