Lipoprotein(a) and apolipoprotein(a) in a New World monkey, the common marmoset (Callithrix jacchus). Association of variable plasma lipoprotein(a) levels with a single apolipoprotein(a) isoform.

Abstract

In an earlier report (Chapman et al, Biochemistry 1979;18:5096-5108), we suggested that the common marmoset may represent an important model for the study of human plasma lipoprotein metabolism. We now extend the interest of this monkey model to the study of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]). Density gradient ultracentrifugal fractionation of marmoset plasma revealed a bimodal distribution of Lp(a), with one peak of concentration occurring in association with very low density lipoproteins (VLDLs) and a second in the density range 1.040-1.080 g/ml. The dense Lp(a) subspecies displayed physicochemical properties (chemical composition, particle size, and electrophoretic mobility) that closely resembled those of its counterpart in humans and baboons but that were distinct from those of low density lipoprotein (LDL). Furthermore, the particle size of marmoset Lp(a) was invariant (31 nm) over the density interval 1.040-1.080 g/ml, whereas that of LDL decreased progressively with an increase in density (-26-25.2 nm). Use of polyclonal and monoclonal antibodies to human apo(a) and of a polyclonal antibody to marmoset Lp(a) allowed immunologic identification of a single apo(a) isoform in the marmoset whose size was similar to that of apo B-100; apo(a) and apo B-100 were associated in Lp(a) particles by a disulfide linkage. The total protein mass of apo-Lp(a) was estimated to be 800,000 or more by electrophoresis in sodium dodecyl sulfate-polyacrylamide-agarose gels. The amino acid compositions of marmoset and human apo(a) resembled each other but were distinct from those of the corresponding forms of apo B-100. Immunologic evidence is provided for a high degree of cross reactivity between apo(a) in marmosets, baboons, and humans, supporting the idea of the existence of a marked degree of structural homology between these proteins. In addition, electroimmunoblotting of marmoset apo(a) and marmoset plasminogen showed that these proteins shared certain epitopes in common, suggesting that marmoset apo (

Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.

“…In this article we have evaluated the segregation of the apo(a) gene and plasma Lp(a) levels in 48 Caucasian families and found that virtually all the inter-individual variation in plasma Lp(a) levels was attributable to the genomic region encoding the apo(a) glycoprotein. It had been clear from previous family studies that plasma Lp(a) levels are largely genetically determined; prior estimates of the heritability of plasma Lp(a) levels have ranged from 0.75 to 0.98 (15,17,40,41) which is comparable to our estimate of 0.85 (±8%).…”

“…Plasma Lp(a) concentrations were measured in a sample of 288 fasting individuals from 48 Caucasian American families living in the greater Dallas, Texas area. Families in which both parents and at least three children were available for sampling were selected for study.…”

Review: Epidemiology of Lp(a) lipoprotein: its role in atherosclerotic/thrombotic disease

“…However, there is far from a linear relationship between small size of the Lp(a) polypeptide chain and high concentration of Lp(a) lipoprotein in serum. Thus, a 100-fold variation in Lp(a) lipoprotein concentration (0.5-49 mg/dl plasma) has been reported in a primate that exhibited only one molecular size of the Lp(a) polypeptide chain (Guo et al 1991). Also, Hobbs and her co-workers have reported evidence that a specific gene (DraIII pattern 3) with a low number of kringle IV repeats is invariably associated with low concentration of Lp(a) lipoprotein (Mancini et al 1995).…”

Errata

“…It is a small sidebar but also important to point out that when you are uncertain as to what you are measuring and sometimes even when you are, interference from the drug or its metabolites can affect the performance of the assay and the level of the analyte you are trying to measure (4). In defense of the authors, it might be well to point out that this is not the first time that Lp(a) has been reported in a species where the data were not reproducible by other investigators (5,6). All of this is not so cut and dry.…”