Comparison of the LDL-receptor binding of VLDL and LDL from apoE4 and apoE3 homozygotes

Compared with apolipoprotein E3 (apoE3), apoE2 is less effective in mediati ng the binding of lipoproteins to the low-density lipoprotein (LDL) recepto r. The influence of the E4 isoform, which is associated with adverse effect s on plasma lipids and coronary heart disease, is less clear. We compared t he ability of very low density lipoprotein (VLDL) and LDL from paired E4/4 and E3/3 subjects to compete against I-125-labeled LDL for binding with the LDL receptor on cultured fibroblasts and Hep G2 cells. The concentrations of VLDL or LDL required to inhibit binding of I-125-LDL by 50% (IC50, mu g apoB/ml) were determined, and results were assessed in terms of an IC50 rat io, E4/4 IC50 relative to E3/3 IC50, to reduce the influence of interassay variability. In Hep G2 cells, E4/4 VLDL was more effective than E3/3 VLDL i n competing for the LDL receptor, the IC50 ratio being lower than unity (0. 73 +/- 0.31, P < 0.05, two-tailed t-test). IC50 values themselves were marg inally lower in E4/4 than E3/3 subjects (3.7 +/- 1.3 vs. 6.1 +/- 3.7, P < 0 .08). However, there was no difference between E4/4 and E3/3 VLDL in compet ing for the LDL receptor on fibroblasts or between E4/4 and E3/3 LDL in com peting for the LDL receptor on either cell type. These results suggest that inheritance of apoE4 is associated with an increased affinity of VLDL part icles for LDL receptors on hepatocytes and may partly explain the influence of the E4 isoform on lipid metabolism.