Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society

Abstract

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.

Keywords: Cardiovascular disease; Lipoprotein remnants; Residual risk; Triglyceride-rich lipoproteins; Triglycerides.

Formation of triglyceride-rich lipoprotein remnants and their role in atherogenesis. Metabolic scheme for the generation and clearance of triglyceride-rich lipoprotein remnant particles (A). In hypertriglyceridaemia, overproduction and inefficient lipolysis of both very low-density lipoprotein and chylomicrons lead to increased remnant formation. Triglyceride-rich lipoprotein remnants contribute to the initiation and progression of atherosclerotic lesions (B). Particle retention in the subendothelial space is followed by inflammation, cholesterol deposition, and macrophage foam cell formation.

Figure 3

Absolute risk of cardiovascular morbidity as a function of increasing non-fasting plasma triglycerides in the general population. Based on data from more than 100 000 individuals in the Copenhagen General Population Study, as derived from refs.^,,, ASCVD, atherosclerotic cardiovascular disease.

Figure 1

Size and density profile of major apolipoprotein B-containing lipoprotein classes. This schematic depicts the spectrum of apolipoprotein (apo) B-containing lipoproteins (VLDL, IDL, LDL—very low-, intermediate-, and low-density lipoproteins, respectively), their density and size (diameter in nm), distribution, and their content of triglyceride and cholesteryl ester (as percent of mass). The stylized distribution of the relative amount of remnant particles in subjects with optimal triglyceride (<1.2 mmol/L) and elevated triglyceride (3.0 mmol/L) is shown for apoB100 (orange) and apoB48 (blue) containing lipoproteins. The profile of ‘apoB48 remnants’ is based on the apoB48 concentrations in VLDL₁, VLDL₂, and IDL in the late (post-peak) phase of lipid absorption and after an overnight fast, whereas that of ‘apoB100 remnants’ is based on the concentration of apoB100 in VLDL₂ and IDL. Based on data from Björnson et al. CE, cholesteryl ester; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very low-density lipoprotein.

Figure 2

Physicochemical characteristics of remnant lipoproteins. (A) Remnant lipoproteins are partially lipolysed products of lipoprotein lipase action. They have a triglyceride-depleted core and are enriched in cholesteryl esters. The main structural protein is apolipoprotein (apo)B48 in chylomicron remnants and apoB100 in very low-density lipoprotein remnants. A typical normal-sized low-density lipoprotein particle is shown for comparison. (B) Comparison of the cholesterol/apoB molar ratios in remnant-like particles isolated by immunoaffinity gel from the plasma of fasting subjects with Type III dyslipoproteinaemia, in which remnant particles accumulate, or borderline or moderately elevated triglyceride levels (data extracted from ref⁵). Only traces of remnant particles were detected in subjects with borderline elevated triglyceride levels. apo, apolipoprotein; CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; HSPG, heparan sulphate proteoglycans; LDLr, low-density lipoprotein receptor; LRP1, low-density lipoprotein receptor-related protein 1; mol, molecules; RLP, remnant-like particle; RLP-C, remnant-like particle cholesterol; TG triglyceride; TRL, triglyceride-rich lipoproteins.

Figure 4

Overview of apolipoprotein B lipoprotein metabolism. During absorption of fat from the diet, chylomicrons are generated by the enterocytes in the small intestine, travel via lymphatics, and appear in the bloodstream. Lipidation of a primordial apolipoprotein (apo) B48-containing particle (apoB48, a truncated form of apoB100 made solely in the intestine) is mediated by microsomal triglyceride transfer protein using triglyceride synthesized from absorbed fatty acids. In a similar assembly process, a large triglyceride-rich, apoB100-containing very low-density lipoprotein (VLDL)₁ is made in the liver using a variety of sources for triglyceride synthesis—de novo lipogenesis, fatty acids released from intracellular storage droplets, free fatty acids taken up from the circulation after their release from adipose tissue, and triglyceride fatty acids present in VLDL chylomicron remnants. Chylomicrons and VLDL₁ (and to an extent VLDL₂) compete for the same lipolytic mechanism. Lipoprotein lipase is anchored to the luminal surface of the capillary endothelium in skeletal muscle and adipose tissue by glycophosphatidylinositol-anchored high-density lipoprotein-binding protein-1. This enzyme hydrolyzes triglyceride in the core of the particle releasing fatty acids into the underlying tissue bed. Lipase maturation factor 1 is essential for the secretion of functional lipase from adipose tissue and muscle. ApoCII is an activator (essential cofactor) of lipoprotein lipase, whereas apoCIII is an inhibitor of the enzyme and of remnant particle uptake. The angiopoietin-like proteins 3, 4, and 8 (ANGPTL3, 4, 8) have a tissue-specific role in modifying (inhibiting) lipoprotein lipase action, whereas apoAV increases lipoprotein lipase-mediated lipolysis. Lipolysis of chylomicrons leads to the formation of remnant particles, which are cleared by the liver via the low-density lipoprotein receptors and, based on mouse studies, the low-density lipoprotein receptor-related protein 1. Likewise, VLDL₁ is delipidated to VLDL₂, remnants, and intermediate-density lipoproteins, which are either removed by liver receptors or converted to low-density lipoprotein as the final product. Smaller VLDL₂ is also made by the liver and can be delipidated to intermediate-density lipoprotein and low-density lipoprotein (for more detail see refs^43–45). It should be noted that lipolysis of both chylomicrons and VLDL in adipose tissue and skeletal muscle is neither equally divided nor randomly apportioned but is determined by insulin mediated regulation of lipoprotein lipase in each tissue, with insulin stimulating lipoprotein lipase in adipose tissue and inhibiting it in skeletal muscle. In addition, ANGPTL3 and ANGPTL8 inhibit lipoprotein lipase activity in skeletal muscle in the fed state and ANGPTL4 inhibits lipoprotein lipase activity in white adipose tissue during fasting. FFA, free fatty acids; GPIHBP1, glycophosphatidylinositol-anchored high-density lipoprotein-binding protein-1; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLr, low-density lipoprotein receptor; LMF1, lipase maturation factor 1; LRP1, low-density lipoprotein receptor-related protein 1; MTP, microsomal triglyceride transfer protein; VLDL, very low-density lipoprotein.

Figure 5

Metabolism of remnant lipoproteins. Remnants are a population of particles in the circulation that have been partially lipolysed by lipoprotein lipase. Efficient lipolysis (broad green arrow) leads to rapid conversion to low-density lipoprotein, with little remnant formation. Causes of remnant accumulation are overproduction of triglyceride-rich lipoproteins or compromised (but not completely absent) lipase action (red arrows). ‘Transient’ remnants in the very low-density lipoprotein/intermediate-density lipoprotein range are converted to low-density lipoprotein; chylomicron remnants are not converted to low-density lipoproteins (see Graphical Abstract and Figure 4). Inefficient lipolysis increases the residence time of remnants and they undergo remodelling, acquiring cholesterol (specifically cholesteryl ester by transfer mediated by cholesteryl ester transfer protein), and apolipoprotein (apo) E. This remodelling can lead to a particle that is no longer susceptible to lipolysis—an ‘end-product’ remnant—with a prolonged residence time in the circulation. CETP, cholesteryl ester transfer protein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LpL, lipoprotein lipase; VLDL, very low-density lipoprotein.

Figure 6

Causes of hypertriglyceridaemia in the population. This schematic representation illustrates the distribution of plasma triglyceride levels in a population (adapted from a survey of >100 000 individuals in the Copenhagen General Population Study). The distribution is segmented by colours according to the triglyceride cut-points in Box 1, i.e. optimal triglyceride <1.2 mmol/L (green), borderline elevated, 1.2–1.7 mmol/L (yellow), moderately elevated, 1.7–5.7 mmol/L (pink), and severe or extreme hypertriglyceridaemia, >5.7 mmol/L (brown). (Note plasma samples in this survey were non-fasting whereas cut-points in Box 1 are for fasting values). Increased production of very low-density lipoprotein in the liver is the primary abnormality leading to higher levels of triglyceride-rich lipoproteins and remnants in individuals with borderline/moderately increased plasma triglyceride, whereas decreased lipolysis is the predominant feature at higher triglyceride concentrations, with accumulation of both very low-density lipoprotein and chylomicrons. Individuals with the most severe forms of hypertriglyceridaemia, particularly those with monogenic causes, may have normal production rates and extremely low levels of lipolysis. TG, triglyceride; VLDL, very low-density lipoprotein.

Figure 7

Role of triglyceride-rich lipoproteins and remnants in atherogenesis. Because of their size (<70 nm), chylomicron remnants, very low-density lipoprotein remnants, and intermediate-density lipoprotein can enter the artery wall by transcytosis across the endothelial layer. With elevated plasma levels, rates of influx exceed egress resulting in accumulation of particles in the subendothelial space. These lipoprotein particles can adhere to extracellular matrix (proteoglycans), an interaction enhanced by the presence of apolipoprotein (apo) CIII and apoE on the particle surface. In situ degradation of these particles releases bioactive lipids, which cause endothelial dysfunction and inflammation. Monocyte-macrophages are recruited from the circulation to clear the deposited lipoproteins, and uptake of cholesterol-enriched lipoproteins leads to foam cell formation and the appearance of early lesions (A). With repeated cycles of lipoprotein ingress and macrophage migration, a fatty streak is generated (B). Further cellular changes include migration of medial smooth muscle cells into the lesion area. Eventually an unstable complex plaque forms, which upon surface erosion or mechanical rupture may lead to thrombus formation, and potentially lumen occlusion with an ensuing clinical event. CE, cholesteryl ester; IDL, intermediate-density lipoprotein; VLDL, very low-density lipoprotein.