A study of the structural heterogeneity of low-density lipoproteins in two patients homozygous for familial hypercholesterolaemia, one of phenotype E2/2.

The structural heterogeneity of the low-density lipoproteins (d 1.019-1.063 g ml-1) in two female patients homozygous for familial hypercholesterolaemia, one of phenotype E2/2, has been evaluated using a new ultracentrifugal density gradient procedure. The mass distribution, chemical composition, particle size and heterogeneity, hydrated density and apolipoprotein content of 16 LDL subfractions were determined. By gradient gel electrophoresis, the lighter LDL subfractions (d 1.016-1.037 g ml-1) displayed a single particle species which progressively diminished in size from 24.8 to 22.0 nm with increase in density. By contrast, subfractions of higher density (d greater than 1.037 g ml-1) exhibited two LDL particle species of distinct size; one component decreased in size from 21.8 to 20.4 nm with increase in density, while the second maintained an essentially constant diameter (between 22.5 and 23.5 nm) across these LDL subfractions. Immunoblotting with anti-apo-B100 of LDL subspecies separated by gradient gel electrophoresis showed all particles to contain apo-B100. However, dot-blots and immunoblotting with a monoclonal antibody to lipoprotein (a) (Lp(a)) revealed that the LDL particle subspecies of greatest diameter (22.5-23.5 nm) present in the denser subfractions (d greater than 1.037 g ml-1) also contained the Lp(a) antigen. These findings, taken together with the high plasma Lp(a) levels (greater than 60 mg dl-1) in our patients, raise the possibility that Lp(a) may contribute in a significant manner to the atherogenic process in homozygous familial hypercholesterolaemia.