Abstract-We investigated the influence of apolipoprotein (apo) E-containing particles on LDL receptor binding of large, buoyant LDL subfractions (LDL I) from subjects with predominantly large (phenotype A) and small (phenotype B) LDL particles. Direct binding by human fibroblast LDL receptors was tested at 4°C before and after removal of apoE-containing particles by immunoaffinity chromatography. The binding affinity of total LDL I in phenotype B was greater than that in phenotype A (Kd of 1.83Ϯ0.3 and 3.43Ϯ0.9 nmol/L, respectively, PϽ.05). LDL I from phenotype B subjects had a higher apoE to apoB molar ratio than did that from phenotype A (0.16Ϯ0.04 versus 0.06Ϯ0.02, PϽ.05). Nondenaturing gradient gel electrophoresis of apoE-containing LDL I isolated by immunoaffinity chromatography revealed a substantially larger peak particle diameter than in apoE-free LDL I, and comparison of LDL I composition before and after immunoaffinity chromatography suggested an increase in triglyceride content of apoE-containing particles. After removal of these particles, there was a greater than twofold reduction in LDL receptor affinity of phenotype B LDL (Kd of 1.83Ϯ0.3 to 3.76Ϯ0.6, PϽ.01), whereas in phenotype A no change was observed (Kd of 3.43Ϯ0.9 to 3.57Ϯ0.4, respectively). The receptor affinity of apoE-free LDL I from phenotype A and B subjects did not differ. These findings confirm that large, buoyant LDL particles from phenotype B subjects have a higher LDL receptor affinity than does LDL I from phenotype A subjects and suggest that this difference is due to an increased content of large, triglyceride-enriched, apoE-containing lipoproteins. 1,2 On the basis of differences in LDL subclass profiles as determined by GGE, individuals may be categorized as having a predominance of large (phenotype A) or small (phenotype B) LDL particles.3 Phenotype B is associated with increased plasma triglyceride levels, reduced HDL cholesterol levels, and as much as a threefold increase in risk for coronary artery disease. 4,5 Phenotype B, at least in part, is genetically determined but is also strongly influenced by sex, age, and environmental factors, including abdominal obesity, oral contraceptive use, and dietary fat and carbohydrate intake.
-10We recently evaluated whether differences in the binding of LDL to fibroblast LDL receptors might contribute to the different LDL subclass distributions in phenotype A and B subjects.11 In phenotype A subjects, we found that, consistent with other reports, 12-17 LDL receptor binding affinity was higher in fractions containing LDL of mid-range size and density than in fractions containing either large, buoyant LDL or small, dense LDL. In phenotype B, the binding affinities of both mid-range and small LDL were similar to those for phenotype A, but the affinity for large LDL (ie, LDL I) was significantly greater.11 The apoE content of large, buoyant LDL fractions was also higher in LDL I from phenotype B subjects.
11Particles with additional apoE have been shown to have greater LDL receptor binding ...