The discoveries of Brown and Goldstein revolutionized our understanding of cholesterol metabolism, fundamental to atherosclerosis and its potential prevention and treatment. Since the early findings of the presence of cholesterol in human atherosclerotic plaques in 1910 and the association of low-density lipoprotein (LDL) particles with the development of coronary heart disease (CHD) in 1955, LDL cholesterol has been at the very core of understanding and estimating the risk of CHD.1 The results of this focus on LDL have been impressive, both regarding the understanding of the regulation of cholesterol metabolism and in the translation of these findings to an efficient pharmacological intervention: inhibition of HMG-CoA reductase (HMGCR) in the mevalonate pathway to reduce circulating LDL cholesterol levels, i.e. the statins. These safe and cheap drugs not only reduce heart attacks, but actually prolong life in middle-aged individuals.2 Only more recently the nuances in lipoprotein metabolism and their potential effects on the development of atherosclerosis and its prevention have come into play on the central stage. Recent large-scale genetic evidence, via Mendelian randomization analyses, has played a crucial role in increasing our knowledge on the causal (or the lack thereof) relationships of the central molecular players associated with CHD pathogenesis.3 These include the established causal roles of triglyceride-rich lipoproteins (or remnant cholesterol)4 and lipoprotein(a)5 in CHD and the unfortunate saga related to high-density lipoprotein (HDL) cholesterol and the burgeoning indications that, despite strong and consistent observational associations, HDL cholesterol does not seem to be causal for CHD and therefore not an appropriate drug target.3 Mendelian randomization analyses have also been increasingly used to assess the cardiometabolic outcomes and systemic metabolic effects of drug targets.3,6 These include inhibition of Niemann-Pick C1-Like 1 (NPC1L1) receptor,7 inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9)8,9 and cholesteryl ester transfer protein (CETP)10,11 as well as inhibition of HMGCR.7–12 Many of the genetic approaches are linked with the latest randomized controlled trials for new drug targets which have revealed some intriguing findings in relation to lipoprotein lipids and the risk of CHD, for example the inhibition of CETP and the REVEAL trial.6,10,11,13 The most recent Mendelian randomization study by Ference at al.14 sheds new light on the pressing issue of the relative importance and interplay of circulating cholesterol and triglycerides and their role in the development and risk of CHD. In this extensive and elegant work, the authors compared the effects of genetic modification of lipoprotein lipase (LPL, primarily lowering triglycerides) with the well-known (genetic) modifications of the LDL receptor (LDLR) pathway (targeted by statins and PCSK9 inhibitors, primarily lowering LDL cholesterol). The authors convincingly showed that triglyceride-lowering LPL variants and LDL cholesterol-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in apolipoprotein B (apoB).14 In a nutshell, this means that the clinical benefit of lowering circulating triglycerides as well as LDL cholesterol appears to be proportional to the absolute change in apoB concentration, i.e. to the number of apoB-containing lipoprotein particles. Thus, the lipoprotein particles containing apoB would be the culprit, not the lipids per se that are transported in these various lipoprotein particles. Since both very-low-density lipoprotein (VLDL) particles and LDL particles contain a single copy of the apoB molecule, it can also be deduced that ‘VLDL particles are as atherogenic as LDL particles’.15 These recent results by Ference and co-workers14 do not come out of the blue. Similar indications and interpretations have already been presented16,17 and, for example, the reason for the ‘success’ of the CETP inhibitor anacetrapib in the REVEAL trial pinpoints exactly this same issue—the reduction in the risk of CHD would primarily be due to apoB-containing lipoprotein particles.6,10,11,13 After the 1985 Nobel Prize in Physiology or Medicine for Brown and Goldstein for their discoveries concerning the regulation of cholesterol metabolism, the molecular biology research of atherosclerosis has flourished.1 In fact, there is currently a plethora of molecular evidence, conveyed nicely by the ‘response-to-retention hypothesis’, to support a straightforward and coherent aetiological explanation for the principal culprit of atherosclerosis and CHD being apolipoprotein B-containing lipoprotein particles.16 The ‘response-to-retention hypothesis’ in relation to circulating apoB-containing lipoprotein particles is illustrated in Figure 1. The initiating event in atherogenesis is the retention of apoB-containing lipoprotein particles within the arterial wall. Negatively charged proteoglycans in the extracellular matrix of the intima bind and trap apoB-containing lipoprotein particles via electrostatic interactions; specific binding areas have been identified in apoB-100 (the full-length hepatic form of apoB), in apoB-48 (the truncated intestinal form of apoB) and in apolipoprotein E. The maladaptive local consequences of the particle retention not only include accumulation of those lipid molecules carried in the particles, but also a prolonged exposure of these particles to local enzymes and other factors within the vessel wall. The environment is indeed hostile for the trapped particles and they get modified, this including aggregation and fusion of the particles which results in generation of multilamellar membrane material in the intima.18 This enhances their retention, and the heterogeneous protein-lipid material is taken up by macrophages and vascular smooth muscle cells leading to foam-cell formation and eventually to the growth of atherosclerotic plaques.16,18,19 Simplified illustration of the ‘response-to-retention hypothesis’ of atherosclerosis development in relation to circulating apolipoprotein B-containing lipoprotein particles. Circulating apolipoprotein B (apoB)-containing lipoproteins can be divided into four main categories: large and small very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) particles.6 Due to their size, the largest VLDL particles cannot enter the arterial intima, but the other smaller apoB-containing lipoproteins can. Electrostatic proteoglycan-apoB interactions cause entrapment of some particles that diffuse into the intima. This initiates a vicious circle of molecular consequences, for example: the particles get modified, fuse and result in multilamellar membrane material, avidly taken up by macrophages and vascular smooth muscle cells. This leads to foam-cell formation and eventually to the growth of atherosclerotic plaques.1,16,19 There is a single copy of an apoB molecule in each particle. However, the lipid contents vary both in the volume and in the relative content of lipid species. Approximate percentages of triglycerides (TG) and total cholesterol (C; including both free cholesterol and cholesteryl ester molecules) of all lipids in each lipoprotein subclass particle are given in the figure.12 Cholesterol and triglyceride molecules, in varying combinations, always accompany the apoB molecule.18 The lipoprotein subclass profile is individual and there is extensive variation in the relative amounts of the particles; at the population level, the average approximate portions of apoB-containing particles are 75% in LDL, 15% in IDL, 10% in small VLDL and less than 1% in large VLDL.6,9 However, in for example hyperlipidaemia or in a post-prandial state, these proportions may be remarkably different at an individual level. In addition, many chylomicron remnants (with part of chylomicron triglycerides lipolyzed in the circulation with the accompanying reduction in the particle size) are in the size category of particles that can enter the intima, with their apoB-48 molecule also binding to proteoglycans.4,16 Lipoprotein(a) particles, specially modified apoB100-containing lipoprotein particles, with an added glycoprotein apo(a) molecule of a varying size, are also anticipated to enter the intima and have similar characteristics than other apoB-containing particles.5 Nonetheless, without the apoB molecule none of these transport vehicles would exist, and all the current accumulating evidence concordantly points towards the apoB molecule being the culprit in the ‘response-to-retention hypothesis’ of atherosclerosis.14,16 The ‘response-to-retention hypothesis’ and the related molecular phenomena were originally formulated and studied mainly in relation to LDL particles. This is natural, due to the evident key role of LDL particles in the processes. However, population characteristics have changed quite dramatically since the early days of cholesterol and atherosclerosis research. In the modern society, people have spurious and energy-dense eating patterns, i.e. are mostly living in a non-fasting state. The metabolic consequences of this (together with many other factors, e.g. low physical activity) are immense and also relate to the risk factors of CHD. In addition to many general clinical conditions such as obesity, hypertension, insulin resistance and type 2 diabetes, the average population lipid profiles have changed accordingly. This means an increasingly important role of high circulating triglycerides and the related apoB-containing lipoprotein particles in the risk of CHD.17,20 Importantly, it has been consistently shown that triglyceride-rich particles behave fundamentally the same way as LDL particles in relation to the ‘response-to-retention hypothesis’ and the development of atherosclerosis.4,17,19,20 The decades of molecular biology research on the fundamentals of atherosclerosis and the development of coronary heart disease have now united with the recent evidence from genetics, Mendelian randomization analyses and drug trials. The message is unanimous: the culprit for the initiation and development of atherosclerosis is the carrier, the apoB-containing lipoprotein particle. Importantly, however, the apoB protein molecule does not exist in a native and functional form without lipids.18 As a corollary of this, when there is an apoB molecule, there are also lipids: in a large VLDL particle there may be over ten thousand lipid molecules per one apoB, and in a small LDL particle around a thousand lipid molecules per one apoB molecule. The relative percentages of triglycerides and cholesterol within these lipids vary according to the lipoprotein subclass category: in the largest VLDL particles, over 70% of the lipids can be triglycerides and only less than 20% cholesterol. On the contrary, in small LDL particles more than 60% of lipids can be cholesterol (mainly in the transportable form of cholesteryl ester molecules) and only less than 10% triglycerides (Figure 1). So the various lipid loads are always inevitably there, but the apoB molecule inherently determines the path. Based on all this multifaceted evidence, the refined key role of apoB in the causal chain of molecular players leading to atherosclerosis and CHD is evident. Consequently, apoB should be taken into account when reviewing new clinical recommendations and assigning (combination) therapies and, importantly, when designing and testing new pharmacological interventions.6 It is without doubt that it is going to be difficult for many people to intrinsically accept apoB as the culprit—it is evident that some researchers and clinicians fancy cholesterol more than triglycerides, and vice versa. Currently the ‘apoB-school’ appears to be lurking in the shadows. Lipids per se also have a long-standing tradition in both research and clinical risk assessment of CHD. However, with all the substantial new evidence, there should not be any real reason to stick to the past with limited views on atherosclerosis and the risk of CHD—it is LDL cholesterol, it is remnant cholesterol, it is lipoprotein(a), it is triglycerides—all these nonetheless are just partial views on how the lipoprotein subclass profile is reflected in different metabolic situations. The number of apoB-containing lipoprotein particles can explain them all in a coherent and a simple way. I would think we should really cherish the simplicity of Mother Nature when offered this once. M.A.K. is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1158958). He also works in a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1). The Baker Institute is supported in part by the Victorian Government’s Operational Infrastructure Support Program.
No takes yet. Share an insight, caveat, or question.
Mika Ala‐Korpela (2019) studied this question.
Synapse has enriched 2 closely related papers on similar clinical questions. Consider them for comparative context: