Lipoprotein (a): a historical appraisal

Abstract

Initially, lipoprotein (a) [Lp(a)] was believed to be a genetic variant of lipoprotein (Lp)-B. Because its lipid moiety is almost identical to LDL, Lp(a) has been deliberately considered to be highly atherogenic. Lp(a) was detected in 1963 by Kare Berg, and individuals who were positive for this factor were called Lpa⁺ Lpa⁺ individuals were found more frequently in patients with coronary heart disease than in controls. After the introduction of quantitative methods for monitoring of Lp(a), it became apparent that Lp(a), in fact, is present in all individuals, yet to a greatly variable extent. The genetics of Lp(a) had been a mystery for a long time until Gerd Utermann discovered that apo(a) is expressed by a variety of alleles, giving rise to a unique size heterogeneity. This size heterogeneity, as well as countless mutations, is responsible for the great variability in plasma Lp(a) concentrations. Initially, we proposed to evaluate the risk of myocardial infarction at a cut-off for Lp(a) of 30-50 mg/dl, a value that still is adopted in numerous epidemiological studies. Due to new therapies that lower Lp(a) levels, there is renewed interest and still rising research activity in Lp(a). Despite all these activities, numerous gaps exist in our knowledge, especially as far as the function and metabolism of this fascinating Lp are concerned.

Keywords: atherosclerosis; metabolism; myocardial infarction; review.

Fig. 1.

Correlation of the FCRs of Lp(a) to those of LDL. Twelve volunteers were injected simultaneously with ¹²⁵I-labeled Lp(a) plus ¹³¹I-labeled LDL and the decay of radioactivity was measured at different time points up to 1 week. FCR is displayed in pools per day (r = 0.853; P < 0.01). See main text for details.

Fig. 2.

Half-life of Lp(a) in comparison to LDL in hedgehogs. Human Lps were labeled with the nondegradable label, ¹²⁵I tyramine cellobiose, and injected individually into male or female hedgehogs (n = 20). Blood was taken at the indicated time intervals and the radioactivity was measured in a β-counter. See main text for details.

Fig. 3.

Accumulation of Lp(a) in various organs of hedgehogs. Human Lp(a), labeled with ¹²⁵I tyramine cellobiose, was injected into hedgehogs. After 24 h animals were euthanized, the organs were perfused with ice-cold saline, and the radioactivity was counted. For biological screening purposes, some animals received the radiolabeled Lp and 2 h later, blood from donor animals was harvested and reinjected into two “acceptor animals”. After 24 h, the animals were euthanized and the radioactivity of various organs was counted. Values are expressed in percent radioactivity per gram of organ. See main text for details.

Fig. 4.

Accumulation of Lp(a) in various organs (A) in comparison to LDL (B). The experimental setup was the same as described in Fig. 3, but the values are expressed in percent radioactivity accumulated after 24 h in total organs. See main text for details.

Fig. 5.

Models of the assembly of Lp(a) from LDL and apo(a). Today, essentially two alternative possibilities are discussed: an intracellular and an extracellular assembly. Lys-analogs, such as tranexamic acid, inhibit the assembly in vitro and probably also in vivo. ©Medical University of Graz.

Fig. 6.

Cartoon showing the transcriptional regulation of APOA. Influence of bile acids [chenodeoxycholic acid (CDCA) and nicotinic acid]. See main text for details. ©Medical University of Graz.