The biology of lipoprotein(a): From genetics to molecular mechanisms

Lipoprotein(a) [Lp(a)] is a primarily genetically determined, low-density lipoprotein-like particle that plays an important role in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Despite optimal control of traditional lipid levels, elevated lipoprotein(a) [Lp(a)] remains a significant contributor to residual cardiovascular risk, affecting up to 20% of the global population.

We performed a literature search of PubMed/Medline and Google Scholar until July 2025 to provide a comprehensive overview of the genetics, structure, metabolism, and molecular mechanisms underlying Lp(a)'s pathogenicity.

Structurally, Lp(a) consists of an LDL-like core covalently bound to apolipoprotein(a) [apo(a)], a polymorphic glycoprotein characterized by kringle IV type 2 (KIV-2) repeat variability. This copy number variation is the primary determinant of apo(a) isoform size and plasma Lp(a) levels. Small isoforms are produced more efficiently, resulting in higher concentrations. Lp(a) is synthesized in hepatocytes, and its plasma levels are predominantly governed by production rather than clearance. It carries a high burden of oxidized phospholipids (OxPLs), which confer pro-inflammatory and pro-atherogenic properties. Lp(a) promotes arterial inflammation, endothelial dysfunction, monocyte activation and impaired fibrinolysis via competition with plasminogen. It also plays a direct pathogenic role in valvular calcification by delivering OxPLs and autotaxin to valve interstitial cells, triggering osteogenic signaling cascades.

While environmental factors such as inflammation and hormonal status can transiently modulate levels, genetic variation overwhelmingly dictates lifelong Lp(a) burden. As novel agents targeting Lp(a) enter late-stage clinical trials, mechanistic insights into Lp(a) biology will be essential to risk stratification and future clinical management.