Effects of ApoE genotype on ApoB-48 and ApoB-100 kinetics with stable isotopes in humans.

Subjects with the apolipoprotein (apo) E4 allele have been shown to have higher low density lipoprotein (LDL) cholesterol and apoB levels than do subjects with the other alleles. To elucidate the metabolic mechanisms responsible for this finding, we examined the kinetics of apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and LDL by using a primed constant infusion of [5,5,5-(2)H(3)]leucine in the fed state (hourly feeding) during consumption of an average American diet in 18 normolipidemic subjects, 12 of whom had the apoE3/E3 genotype and 6, the apoE3/E4 genotype. Lipoproteins were isolated by ultracentrifugation and apolipoproteins, by sodium dodecyl sulfate gels; isotope enrichment was assessed by gas chromatography-mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II software. Compared with the apoE3/E3 subjects, the apoE3/E4 subjects had significantly higher levels of total apoB, 100. 1+/-17.8 versus 135.4+/-34.0 mg/dL (P=0.009), and significantly higher levels of LDL apoB-100, 88.1+/-19.2 versus 127.5+/-32.7 mg/dL (P=0.005), respectively. The pool size of TRL apoB-48 was 17.4% lower for apoE3/E4 subjects compared with apoE3/E3 subjects due to a 33.3% lower production rate (P=0.28). There was no significant difference in the TRL apoB-48 fractional catabolic rate (5.1+/-2.2 versus 5.0+/-2.1 pools per day). The pool size for VLDL apoB-100 was 36% lower for apoE3/E4 subjects compared with apoE3/E3 subjects due entirely to a 30% lower production rate (P=0.04). The LDL apoB-100 pool size was 57.8% higher (P=0.003) for apoE3/E4 subjects compared with apoE3/E3 subjects due to a 35.5% lower fractional catabolic rate of LDL apoB-100 (P=0.003), with no significant difference in production rate. In addition, 77% of VLDL apoB-100 was converted to LDL apoB-100 in apoE3/E4 subjects compared with 58% in apoE3/E3 subjects (P=0.05). In conclusion, the presence of 1 E4 allele was associated with higher LDL apoB-100 levels owing to lower fractional catabolism of LDL apoB-100 and a 33% increase in the conversion of VLDL apoB-100 to LDL apoB-100.