Apolipoprotein E polymorphism and the distribution profile of very low density lipoproteins; an influence of the E4 allele on large (Sf > 60) particles.
Very low density lipoprotein (VLDL) distribution and composition have been examined as a function of apo E genotype (E2/2 + E2/3 vs. E3/3 vs. E3/4 + E4/4) in healthy, normolipaemic subjects. Apo E genotype had a marked impact on plasma concentrations of apo E rich VLDL, but no influence on concentrations of apo E free particles. Thus, there was a trend to lower concentrations of apo E rich total VLDL in apo E4 carriers (mg/dl; E2, 49.1 +/- 35.2; E3, 52.5 +/- 30.9; E4 35.2 +/- 22.3; ANOVA P = 0.16; when comparing E4 with E2 + E3, P = 0.06). Consequently, there were highly significant differences between apo E-defined subgroups in terms of the percentage distribution of bound and non-bound fractions (% total VLDL non-bound to apo E: E2, 44.0 +/- 12.7%; E3, 39.7 +/- 8.7%; E4 51.0 +/- 12.2%; ANOVA P = 0.007). Subfractionation of VLDL into density subclasses revealed that genotype differences were restricted to large VLDL (Sf > 60). Significantly lower concentrations of apo E-rich particles were observed in E4 carriers for VLDL-1 Sf 400-100 (ANOVA P = 0.004) and VLDL-2 (P = 0.009) but not for small VLDL-3 Sf 60-20 (P = 0.34). No differences in plasma concentrations of apo E free VLDL were observed between genotype subclasses across the density spectrum. Compositional differences between the apo E defined VLDL were also evident for the core lipids. Apo E containing VLDL was enriched in esterified cholesterol and depleted in triglycerides compared to apo E poor VLDL: the difference became more marked with increasing density of the particles. Lipoprotein composition was not modulated to any great extent by apo E genotype. In patients with familial hypercholesterolaemia, relative concentrations of apo E rich, large VLDL were significantly higher than in controls. Treatment lowered concentrations of both apo E rich and apo E free VLDL but led to a greater relative enrichment of large VLDL in apo E containing particles. Apo E polymorphism appears to influence plasma concentrations of VLDL particles. The data are consistent with more pronounced receptor-mediated elimination of apo E4 containing VLDL. This may be a contributory factor to the down regulation of receptor activity which is suggested to be of major importance in provoking higher cholesterol levels associated with the apo E4 isoform.
Department of Internal Medicine, University Hospital, Geneva, Switzerland.
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Bioletto
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Fontana
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Darioli
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James
D000328:Adult; D000483:Alleles; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000097:blood; D010316:Particle Size; D011110:Polymorphism, Genetic / Q000235:genetics*; D014461:Ultracentrifugation
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL