The functions of apolipoproteins and lipoproteins in health and disease

Abstract

Lipoproteins and apolipoproteins are crucial in lipid metabolism, functioning as essential mediators in the transport of cholesterol and triglycerides and being closely related to the pathogenesis of multiple systems, including cardiovascular. Lipoproteins a (Lp(a)), as a unique subclass of lipoproteins, is a low-density lipoprotein(LDL)-like particle with pro-atherosclerotic and pro-inflammatory properties, displaying high heritability. More and more strong evidence points to a possible link between high amounts of Lp(a) and cardiac conditions like atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis (AS), making it a risk factor for heart diseases. In recent years, Lp(a)'s role in other diseases, including neurological disorders and cancer, has been increasingly recognized. Although therapies aimed at low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) have achieved significant success, elevated Lp(a) levels remain a significant clinical management problem. Despite the limited efficacy of current lipid-lowering therapies, major clinical advances in new Lp(a)-lowering therapies have significantly advanced the field. This review, grounded in the pathophysiology of lipoproteins, seeks to summarize the wide-ranging connections between lipoproteins (such as LDL-C and HDL-C) and various diseases, alongside the latest clinical developments, special emphasis is placed on the pivotal role of Lp(a) in cardiovascular disease, while also examining its future potential and mechanisms in other conditions. Furthermore, this review discusses Lp(a)-lowering therapies and highlights significant recent advances in emerging treatments, advocates for further exploration into Lp(a)'s pathogenic mechanisms and its potential as a therapeutic target, proposing new secondary prevention strategies for high-risk individuals.

Keywords: Apolipoproteins; Cardiovascular disease; Lipoproteins; Lp(a); Therapeutic target.

Fig. 1

Illustrative diagram of lipid transport and metabolic pathways. The figure shows the lipid processing pathways through the gut, liver and peripheral tissues. Chylomicrons from the diet are formed in the epithelial cells of the small intestine, and after being broken down by lipoprotein lipase, they transport dietary triglycerides and cholesterol to adipose and muscle tissues. VLDL, synthesized in the liver, carries triglycerides that are progressively hydrolyzed to become LDL, while HDL promotes the reverse transport of cholesterol back to the liver. HDL, High-density lipoprotein; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein

Fig. 2

Illustration of the structure of Lp(a). Lp(a) mainly consists of apoB-100 protein, a lipid core (triglycerides, cholesterol esters, free cholesterol), and Apo(a).Apo(a) is encoded by the LPA gene, which is highly homologous to the plasminogen gene, and contains a Kringle (K) IV domain (KIV 1–KIV 10), a Kringle V (KV) domain, and an inactive protease domain. Lp(a), Lipoprotein(a); Apo(a), Apolipoprotein(a); KIV, kringle IV; KV, kringle V

Fig. 3

Lp(a) in atherosclerosis progression. This diagram demonstrates how Lp(a) contributes to the formation of atherosclerotic plaques. LDL and Ox-LDL accumulate in the arterial intima, triggering monocyte recruitment and differentiation into macrophages. Macrophages engulf Ox-LDL, forming foam cells and releasing inflammatory cytokines such as TNF-α and IL-6, which promote further plaque development. Lp(a) promotes this process by enhancing monocyte adhesion, oxidative stress, and platelet aggregation, increasing the risk of plaque rupture and thrombosis. Lp(a),Lipoprotein(a);LDL, low-density lipoprotein; Ox-LDL, oxidized low-density lipoprotein

Fig. 4

Associations of Lp(a) with Cardiovascular Diseases. This diagram illustrates the role of elevated Lp(a) levels in various cardiovascular conditions. Lp(a) is linked to atherosclerotic coronary disease, calcific aortic valve disease, percutaneous coronary interventions, atrial fibrillation, heart failure, and hypertension. Lp(a), Lipoprotein(a)

Fig. 5

Association of Lp(a) with Various Diseases. This illustration shows the potential links between elevated Lp(a) levels and a range of diseases. High levels of Lp(a) are associated with cardiovascular disease, nervous system diseases, peripheral arterial disease, diabetes, autoimmune diseases, chronic renal disease, and cancer. These associations suggest that Lp(a) plays a role beyond cardiovascular health, impacting multiple organ systems and disease processes. Lp(a), Lipoprotein(a)