Metabolism of lipoprotein(a): new findings, implications and outstanding issues

DOI:10.1097/MOL.0000000000000678 composed of one molecule of the glycoprotein apolipoprotein(a) (apo(a)) covalently bound to apoB-100-containing LDL-like particles [1]. Genetic, epidemiological and Mendelian randomization studies have established Lp(a) as the most common inherited causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis [2,3 && ]. Recent clinical outcomes trials employing proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) also suggested ASCVD benefits from lowering Lp(a) in high-risk patients [4 & ,5 & ]. However, the metabolism of Lp(a) in humans remains enigmatic and requires further investigation [3 && ]. Apo(a) and apoB components of Lp(a) are synthesized in the liver [1]. There is controversy concerning the location where apo(a) and apoB-100 are assembled and whether the transport of apo(a) to apoB-100 is coupled [5 & ]. Data from ex-vivo cellular models, such as isolated hepatocytes or HepG2 cells, are inconclusive possibly owing to differences in experimental settings [3 && ,6 & ]. Understanding the dynamics of Lp(a) metabolism in vivo is important. Using stable isotope labelling, Ma et al. [7 & ] investigated the metabolism of apo(a) and apoB within plasma Lp(a) during the postabsorptive state in statin-treated patients with elevated and normal Lp(a) concentrations [8]. The tracer curves for both protein components of Lp(a) were found to be superimposable, supporting the notion that apo(a) and apoB may be assembled within or on the surface of hepatocytes. That apo(a) and apoB proteins within Lp(a) particles have similar fractional catabolic rates also reflects a tight coupling of both protein components of the Lp(a) particle in the circulation at both high and low plasma Lp(a) concentrations. However, this finding is contrary to the previous kinetic studies carried out in the fed state that show the turnover of apo(a) was slower than apoB within the Lp(a) particle [8,9]. The reason for the discrepancy remains unclear, but may relate to an increase in the exchange of apo(a) between Lp(a) and triglyceride-rich lipoprotein (TRL) particles. Circulating concentrations of Lp(a) are largely genetically determined [1,2,3 && ]. However, there is