Unraveling the Complexities of the Lipoprotein(a) Particle and its Metabolism

Abstract

Lipoprotein (a) [Lp(a)], was discovered more than 60 years ago, however, its link to human disease has just begun to unfold. Recent findings in large genome association studies and Mendelian randomization studies have highlighted its role as a causal risk factor in coronary and atherogenic vascular disease. Despite years of research into the mechanisms regulating plasma levels of Lp(a), specific sites and pathways of regulation are poorly characterized. Lp(a) contains two main apolipoproteins, apolipoprotein (a) [apo(a)] and apolipoprotein B100 (apoB100), these are bound by covalent bounds but also weak lisine binding sites are present. The most significant determinant of the level of Lp(a) is the number of DNA-base repeats coding a highly polymorphic sequence of the LPA gene called Kringle IV Type 2 (KIV-2). Importantly, the number of KIV-2 repeats range from about 3-40 resulting in a range of apo(a) mass from 200 – 700 kDA. Almost all individuals, therefore, have two apo(a) isoforms that differ in the size and the size of the apoB bound to the apo(a) has not been well characterize. The mechanism(s) by which KIV-2 isoform size affect Lp(a) concentrations remain minimally defined. Previous studies, using isolated and exogenously radio-iodinated apo(a) isoforms, indicated that the hepatic secretion rate (SR) of apo(a), rather than its fractional clearance rate (FCR), determined plasma levels of Lp(a), and that smaller isoforms (fewer KIV-2 repeats) were associated with greater SRs and higher plasma levels of Lp(a). However isoform size does not account for all the variation in plasma Lp(a) concentration. Indeed, more recent studies using stable isotopes by our group and by others provide a much more complex picture. We will present data on recently completed mechanistic studies using stable isotope in human volunteers with high and low levels of Lp(a). The studies describe the clearance and production of apo(a) and apoB100 from isolated Lp(a). Additionally proteomic composition of the isolated Lp(a) particles and isoforms and the implications of these proteins on disease will be discussed. The studies presented will highlight the complexity of Lp(a) and provide novel insights into the regulation of this cardiovascular risk.