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 hi gher low density lipoprotein (LDL) cholesterol and apoB levels than do subj ects with the other alleles, To elucidate the metabolic mechanisms responsi ble for this finding, we examined the kinetics of apoB-48 within triglyceri de-rich lipoproteins (TRLs) and of apoB-100 within very low density lipopro tein (VLDL), intermediate density lipoprotein (IDL), acid LDL by using a pr imed constant infusion of [5,5,5-H-2(3)]leucine in the fed state (hourly fe eding) 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 chroma tography-mass spectrometry. Kinetic parameters were calculated by multicomp artmental modeling of the data with SAAM II software, Compared with the apo E3/E3 subjects, the apoE3/E4 subjects had significantly higher levels of to tal apoB, 100.1 +/- 17.8 versus 135.4 +/- 34.0 mg/dL (P = 0.009), and signi ficantly 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% lo wer for apoE3/E4 subjects compared with apoE3/E3 subjects due to a 33.3% lo wer 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 subje cts 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) fo r apoE3/E4 subjects compared with apoE3/E3 subjects due to a 35.5% lower fr actional catabolic rate of LDL apoB-100 (P = 0.003), with no significant di fference in production rate. In addition, 77% of VLDL apoB-100 was converte d to LDL apoB-100 in apoE3/E4 subjects compared with 58% in apoE3/E3 subjec ts (P = 0.05), In conclusion, the presence of 1 E4 allele was associated wi th higher LDL apoB-100 levels owing to lower fractional catabolism of LDL a poB-100 and a 33% increase in the conversion of VLDL apoB-100 to LDL apoB-1 00.