Preferential cholesteryl ester acceptors among the LDL subspecies of subjects with familial hypercholesterolemia

Elevated cholesteryl ester transfer protein-mediated transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) may contribute to the atherogenicity of LDL in subjects with familial hypercholesterolemia (FH). To identify the major CE acceptors among LDL subspecies, we investigated the qualitative and quantitative features of CE transfer and exchange to LDL on incubation of plasma under physiological conditions. LDL subspecies were fractionated by density-gradient ultracentrifugation. Both mass transfer and exchange of HDL CE to and with very-low-density lipoprotein plus intermediate-density lipoprotein and LDL were linear for the first 6 hours of incubation. Thereafter mass transfer ceased, but exchange continued at a comparable rate. The rate of CE mass transfer to apolipoprotein B-containing lipoproteins was significantly enhanced in heterozygous FH subjects compared with normolipidemic individuals (91.6±28.2 versus 52.9±19.6 μg CE/h per milliliter plasma, FH versus normal subjects, P<.02). In FH subjects the predominant LDL subspecies (LDL 3 and 4, d= 1.029 to 1.050 g/mL) accounted for 59.7±9.2% of the total CE transferred to LDL from HDL. By contrast, expression of CE mass transfer relative to the mass of each lipoprotein acceptor showed the triglyceride (TG)-rich (10.7% to 17.3%), light LDL subspecies (LDL 1 and 2, d= 1.019 to 1.029 g/mL) to represent the preferential CE acceptors (LDL 1 and 2, 94.8 to 136.5 Mg CE/mg LDL mass; LDL 3 through 5 [d=1.029 to 1.063 g/mL], 47.1 to 64.1 μg CE/mg LDL mass). In comparison, TG-rich (11.4%) LDL-1 in normolipidemic subjects was the most active acceptor of CE from HDL (LDL-1, 99.4±44.3 and LDL 2 through 5, 52.7 to 69.2 μg CE/mg LDL mass). The capacity of LDL subspecies to accept CE from HDL was correlated with the relative content of TG in the LDL (r=.5, P<.0001); the TG-rich particles were the preferred CE acceptors. The quantitative features of CE transfer to LDL subspecies are determined principally by the concentration of acceptor particles (r=.75, P<.0001), while the TG content of LDL appears to be the major qualitative determinant of CE trans-fer.