Abstract
Lipoprotein(a) [Lp(a)], aka “Lp little a”, was discovered in the 1960s in the lab of the Norwegian physician Kåre Berg. Since then, we have greatly improved our knowledge of lipids and cardiovascular disease (CVD). Lp(a) is an enigmatic class of lipoprotein that is exclusively formed in the liver and comprises two main components, a single copy of apolipoprotein (apo) B-100 (apo-B100) tethered to a single copy of a protein denoted as apolipoprotein(a) apo(a). Plasma levels of Lp(a) increase soon after birth to a steady concentration within a few months of life. In adults, Lp(a) levels range widely from <2 to 2500 mg/L. Evidence that elevated Lp(a) levels >300 mg/L contribute to CVD is significant. The improvement of isoform-independent assays, together with the insight from epidemiologic studies, meta-analyses, genome-wide association studies, and Mendelian randomization studies, has established Lp(a) as the single most common independent genetically inherited causal risk factor for CVD. This breakthrough elevated Lp(a) from a biomarker of atherosclerotic risk to a target of therapy. With the emergence of promising second-generation antisense therapy, we hope that we can answer the question of whether Lp(a) is ready for prime-time clinic use. In this review, we present an update on the metabolism, pathophysiology, and current/future medical interventions for high levels of Lp(a).
Highlights
Atherosclerosis is a chronic inflammatory lipid-fueled disease of the arteries that is initiated very early in childhood and mediated by innate and adaptive immune responses
Hypercholesterolemia, for instance, increases the permeability of the vessel walls and initiates the pathogenesis of the disease [4]. e Framingham study showed that low-density lipoprotein cholesterol (LDLC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) are the major independent predictors of future atherosclerotic events [4]. e need to pinpoint further causal risk factors and prospective targets for future interventions is evident [5] by the fact that atherosclerosis is the still the principal cause of cardiovascular disease (CVD) death worldwide despite the decline in mortality rate due to advances Journal of Lipids in its diagnosis, treatment, prevention, and rehabilitation [6, 7]
We know that elevated Lp(a) concentration is a quantitative genetic trait influenced mainly by the LPA gene located on chromosome 6 (6q26–27) [23]. is gene is responsible for the inverse relationship between Lp(a) size, which may vary within and among individuals, and Lp(a) plasma concentration. is size heterogeneity is a unique phenomenon among lipoproteins, which usually have constant masses. e similarity of the two main parts of Lp(a) to the LDL and PLG molecules strongly enhances its atherogenicity
Summary
Atherosclerosis is a chronic inflammatory lipid-fueled disease of the arteries that is initiated very early in childhood and mediated by innate and adaptive immune responses. E new secreted apo(a) is associated with a recently produced apoB-containing TG-abundant molecule to form Lp(a) with very-low-density lipoprotein (VLDL) properties (see Figure 3), which can correspondingly be transformed into a cholesterol-abundant unit with LDL properties [43, 46]. Understanding whether apo(a) binds to LDL within liver cells before or a er secretion to the plasma and which apo-B100 containing lipoprotein is involved in Lp(a) assembly should be the focus of future studies to develop new Lp(a)-lowering therapies
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