Lipoprotein (a). Heterogeneity and biological relevance.

Abstract

Lipoprotein (a), or Lp(a),' discovered by KAre Berg (1) more than 25 years ago, remains today a fascinating subject of re- search both because of its presumed association with athero- sclerotic cardiovascular disease (ASCVD) (2-14) and the many challenges it is offering to geneticists, structural biolo- gists, physiologists, epidemiologists, cardiologists, and clini- cians in general.Among these challenges is the elucidation of the remarkable heterogeneity exhibited by this lipoprotein particle, which is a key for understanding its biology.We will examine the various aspects of this heterogeneity and attempt to provide a global view on past and current knowledge on Lp(a) and identify those controversial areas where intensified research efforts are likely to provide important new advances. Physicochemical basis ofheterogeneityThe heterogeneity of Lp(a) went largely unrecognized until Harvie and Schultz (15) reported that their preparations of Lp(a) had a rather broad sedimentation coefficient distribu- tion, and that 25% of them exhibited a bimodal Schlieren peak.The first systematic study on Lp(a) heterogeneity was carried out in 1984 by Fless et al. (16), who not only confirmed the findings of Harvey and Schultz but by studying individual rather than pooled human blood samples also found that Lp(a) exhibits both inter-and intra-individual density heterogeneity, and that this heterogeneity is accounted for by differences in protein and lipid composition.In the same study, they also observed that apolipoprotein(a) [apo(a)], the specific marker of Lp(a), exhibits size heterogeneity owing to species that have electrophoretic mobility either less than, equal to, or greater than that of apo B100, the protein moiety of low density lipo- protein (LDL).In those studies it was also shown that apo(a) mass contributed to Lp(a) density in that the larger apo(a) was the main component of the denser particles and the smaller apo(a) was preferentially associated to Lp(a) particles of a low buoyant density.The importance of these studies did not be-