Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk

Abstract

In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol. Since then, the evidence has continued to mount in favor of apoB. This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk attributable to the atherogenic apoB lipoprotein particles chylomicron remnants, very low-density lipoprotein, and low-density lipoprotein particles. First, the nature and relative numbers of these different apoB particles will be outlined. This will make clear why low-density lipoprotein particles are almost always the major determinants of cardiovascular risk and why the concentrations of triglycerides and LDL-C may obscure this relation. Next, the mechanisms that govern the number of very low-density lipoprotein and low-density lipoprotein particles will be outlined because, except for dysbetalipoproteinemia, the total number of apoB particles determines cardiovascular risk, Then, the mechanisms that govern the cholesterol mass within very low-density lipoprotein and low-density lipoprotein particles will be reviewed because these are responsible for the discordance between the mass of cholesterol within apoB particles, measured either as LDL-C or non-high-density lipoprotein cholesterol, and the number of apoB particles measured as apoB, which creates the superior predictive power of apoB over LDL-C and non-high-density lipoprotein cholesterol. Finally, the major apoB dyslipoproteinemias will be briefly outlined. Our objective is to provide a physiological framework for health care givers to understand why apoB is a more accurate marker of cardiovascular risk than LDL-C or non-high-density lipoprotein cholesterol.

Keywords: apoB; apolipoprotein B; cardiovascular disease prevention; cardiovascular risk.

Figure 1. apoB lipoprotein particles.

One molecule of apo B₄₈ encircles each chylomicron and chylomicron remnant particle. The chylomicron remnant particle contains less TG but the same amount of cholesterol as the intact chylomicron particle. The difference in TG mass represents the mass of TG delivered to adipose tissue and skeletal muscle. One molecule of apo B₁₀₀ encircles VLDL, LDL, and Lp(a) particles. Lp(a) particles are an LDL particle to which a molecule of apo(a) has been attached. One molecule of apo B₄₈ encircles a chylomicron or chylomicron remnant particle. apoB indicates apolipoprotein B; CE, cholesteryl ester; LDL, low‐density lipoprotein; Lp(a), lipoprotein(a); TG, triglycerides; and VLDL, very low‐density lipoprotein.

Figure 2. Relative numbers of apoB particles.

LDL particles (on the right) are by far the most numerous, whereas chylomicron particles (the large particle on the left) are by far the least numerous. There are, on average, 9 times the number of VLDL particles as the sum of chylomicron and chylomicron particles in the postprandial period but 9 times the number of LDL particles as VLDL particles. Note VLDL and LDL particles can differ in size based on the relative amounts of triglycerides and cholesterol, respectively. LDL particles differ in the mass of cholesterol they contain, and therefore their size, resulting in the subclasses of LDL particles: LDL1, LDL2, and LDL3. In this figure, 1 chylomicron and 1 chylomicron remnant particle are combined, so that the proper relative number of apoB particles in the postprandial period can be illustrated. apoB indicates apolipoprotein B; LDL, low‐density lipoprotein; and VLDL, very low‐density lipoprotein.

Figure 3. VLDL‐LDL particle metabolism.

This figure illustrates schematically the regulation of VLDL and LDL particle number in plasma. VLDL particles are secreted by the liver into the plasma compartment, from which they are either removed directly by the liver after much of their TG have been removed or converted to LDL particles. At steady state, the rate at which VLDL particles are secreted from the liver is equal to the rate at which they are removed from plasma. Once steady state is achieved, either an increase in the rate of production or a decrease in the rate of removal will produce an increased VLDL particle number. Similarly, the rate at which LDL particles are produced at steady state is equal to the rate at which they are removed from plasma. LDL particles are produced by conversion of VLDL to LDL particles and are removed either by a specific clearance pathway or by multiple nonspecific pathways. Almost all LDL particles are cleared from plasma by the liver. Only a small minority are removed by peripheral cells. IDL indicates intermediate‐density lipoprotein; LDL indicates low‐density lipoprotein; TG, triglycerides; and VLDL, very low‐density lipoprotein.

Figure 4. Regulation of VLDL and LDL apoB particle number.

This figure illustrates the metabolic relations among the various VLDL and LDL particles. The liver secretes VLDL1 and VLDL2 particles. VLDL1 particles are the most TG rich and can be converted to VLDL2 particles by hydrolysis of core TG in peripheral tissues. Similarly, VLDL2 particles can be converted to VLDL3 particles, which can be converted to IDL particles or removed by the liver. IDL particles can be converted to LDL1 particles, which, following core lipid exchanges as illustrated in Figure 3, can be converted successively to LDL1, LDL2, and LDL3 particles. VLDL1 are the most TG‐rich particles secreted by the liver; VLDL2 contain an intermediate mass of TG and are also secreted by the liver. VLDL1 and VLDL2 particles can be sequentially converted to VLDL3 particles, which can be converted to IDL particles, which can be converted successively to LDL1, LDL2, and LDL3 particles. apoB indicates apolipoprotein B; CE, cholesteryl ester; IDL, intermediate density lipoprotein; LDL, low‐density lipoprotein; TG, triglycerides; and VLDL, very low‐density lipoprotein.

Figure 5. Lipid exchanges amongst plasma lipoprotein particles.

This figure illustrates the exchange of the core lipids, cholesterol ester (CE) and triglycerides (TG) mediated by CETP among VLDL, LDL, and HDL. If a CE molecule from LDL or HDL is exchanged (yellow arrow) for a TG molecule from VLDL (turquoise arrow), the LDL or HDL particle becomes enriched in TG, but depleted in CE, whereas the VLDL particle loses TG but gains CE. In the case of LDL, the TG is subsequently hydrolyzed, producing a smaller, CE‐depleted LDL particle. Illustrated also is the transfer of free cholesterol from a VLDL particle to HDL as it is being hydrolyzed, where it can subsequently be esterified to form CE. CE indicates cholesterol ester; CETP, cholesterol ester transfer protein; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; TG, triglycerides; and VLDL, very low‐density lipoprotein.

Figure 6. Pathophysiological characteristics of the 4 major apoB dyslipoproteinemic phenotypes.

A, Normal number of VLDL and LDL particles within an arterial lumen. B, Increased number of VLDL particles with an increased number of cholesterol‐rich LDL particles. Familial hypercholesterolemia is the prototypic disorder that represents the extreme manifestations of this phenotype. C, Relative number of VLDL and LDL particles within an arterial lumen in a patient with hyperTG normoapoB. The VLDL particles are enriched in triglycerides or increased in number, but LDL particle number is normal. The net result is that apoB is normal. Familial hypertriglyceridemia is present when this is the dominant phenotype within a family. D, Increased number of VLDL and LDL particles within the arterial lumen of a patient with hyperTG hyperapoB. This occurs because of increased production of VLDL and LDL particles in hyperTG hyperapoB. Familial combined hyperlipidemia represents the expression of this disorder within a family. Levels of apoB are >120 mg/d (>90th percentile) in subjects with familial combined hyperlipidemia. E, Markedly increased number of cholesterol‐enriched VLDL and chylomicron remnants with a normal number of LDL particles in a patient with dysbetalipoproteinemia (type III hyperlipoproteinemia). apoB indicates apolipoprotein B; CE, cholesterol ester; hyperTG hyperapoB, hypertriglyceridemic hyperapoB; hyperTG normoapoB, hypertriglyceridemic normal apoB; LDL, low‐density lipoprotein; TG, triglycerides; and VLDL, very low‐density lipoprotein.