Influence of ApoE Content on Receptor Binding of Large, Buoyant LDL in Subjects With Different LDL Subclass Phenotypes

From the Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley.

Correspondence to Ronald M. Krauss, MD, Lawrence Berkeley National Laboratory, Donner Laboratory, Room 465, University of California, One Cyclotron Rd, Berkeley, CA 94720. E-mail rmkrauss{at}lbl.gov

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 1.83±0.3 and 3.43±0.9 nmol/L, respectively, P<.05). LDL I from phenotype B subjects had a higher apoE to apoB molar ratio than did that from phenotype A (0.16±0.04 versus 0.06±0.02, P<.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 1.83±0.3 to 3.76±0.6, P<.01), whereas in phenotype A no change was observed (Kd of 3.43±0.9 to 3.57±0.4, 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. It is possible that the accumulation of these particles reflects abnormalities in the metabolism of remnant lipoproteins that contribute to atherosclerosis risk in phenotype B subjects.

Key Words: LDL subclasses • apoE • receptor binding • fibroblasts

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