PLASMA-LIPOPROTEINS IN FAMILIAL DYSBETALIPOPROTEINEMIA ASSOCIATED WITH APOLIPOPROTEINS E2(ARG158-]CYS), E3-LEIDEN, AND E2(LYS146-]GLN), ANDEFFECTS OF TREATMENT WITH SIMVASTATIN

Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with familial d ysbetalipoproteinemia (FD) who had apolipoprotein (ape) E2(Arg158-->Cy s) homozygosity (the E2-158 variant, n=6), apoE3-leiden heterozygosity (the E3-Leiden variant, n=6), or apoE2(Lys146-->Gln) heterozygosity ( the E2-146 variant, n=6), with average plasma cholesterol concentratio ns of 8.99+/-1.34 mmol/L, 9.29+/-1.55 mmol/L, and 8.46+/-1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three group s were observed. The lipoprotein profiles of all FD patients were char acterized by higher concentrations of very-low-density lipoprotein (VL DL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5 .90+/-0.53 mmol/L. Major differences between the plasma lipoprotein pr ofiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in ID L cholesterol concentration (1.70+/-0.26, 1.50+/-0.26, 1.05+/-0.36, an d 0.47+/-0.14 mmol/L, respectively), LDL cholesterol concentration (1. 83+/-0.50, 3.09+/-0.32, 3.79+/-0.76, and 3.77+/-0.56 mmol/L, respectiv ely), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98/-0.28, 0.48+/-0.04, 0.28+/-0.09, and 0.12+/-0.03, respectively). Afte r 10 weeks of simvastatin treatment the concentrations of plasma chole sterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 p atients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients w ith the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simva statin therapy lowered plasma activity of cholesteryl ester transfer p rotein but had no significant effect on plasma activity of lecithin: c holesterol acyltransferase. It is concluded that patients with FD due to various apoE Variants have different lipoprotein profiles, mainly w ith regard to IDL and LDL levels, although they have a number of simil ar features of dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholest erol, IDL cholesterol, and LDL cholesterol in the three groups of pati ents studied. It is proposed that apoE-dependent defects of the conver sion of IDL to LDL may be an important mechanism in the pathophysiolog y of FD.