Millions of Americans schedule an annual physical health examination. During their visit, many can expect to get their blood drawn for a standard lipid panel, which ultimately provides the patient with a readout of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TGs). What virtually nobody among them will get is an apolipoprotein B (apoB) test. Yet this is considered the ideal, if not essential, measurement to assess lipoprotein-related atherosclerotic cardiovascular disease (ASCVD) risk, according to recent guidelines and an illuminating review by Dr. Allan Sniderman and his colleagues. In order to appreciate why this matters—and before digging into Sniderman et al.’s review—you need to understand some of the basics of lipids and lipoproteins first, so we’ll break this email into two parts, with this email (Part 1) serving as a primer.If it seems like what follows is “too much,” consider that we are talking about the most prevalent disease in the developed world, and consider, at least for a moment, how much misinformation exists around the ideas of cholesterol.
“We must admit that our opponents in this argument have a marked advantage over us. They need only a few words to set forth a half-truth; whereas, in order to show that it is a half-truth, we have to resort to long and arid dissertations.”
― Frédéric Bastiat, Economic Sophisms, 1848
Lipids are a class of molecules that are not soluble in water and therefore cannot circulate in plasma (the liquid flowing through our arteries and veins), as plasma is 90% water, any more than you can dissolve a tablespoon of olive oil in a glass of water. A lipoprotein is essentially a vehicle that carries these lipids through plasma. A lipoprotein is like a submarine that transports cargo, with the bulk of the cargo consisting of TGs and cholesteryl ester (CE), which is cholesterol with one fatty acid attached to it. The 360-degree hull of this submarine consists of a one-molecule thick layer composed mainly of phospholipids, “free” cholesterol (meaning it’s not bound to a fatty acid), and proteins called apoproteins or apolipoproteins, which wrap around the exterior of the lipoprotein. Apolipoproteins are the “protein” in lipoprotein. This metaphorical submarine is not cigar-shaped like those found in our oceans, but is ball-shaped or spherical found in our plasma, as you can see in Figure 1.
Figure 1. Component parts of a lipoprotein.
The density of lipoproteins were discovered many decades ago by drawing blood into a sealed collection tube, spinning the living daylights out of that tube, a process called ultracentrifugation, and seeing where they settled. Most lipoproteins then became classified by their density. The lipoproteins that sit in the plasma at the top of the tube have the lowest density, and these lipoproteins are called chylomicrons (CMs), which are produced in the small intestine. The other four major classes of lipoproteins are all produced in the liver. In order of density, lowest to highest, they are: very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Among the LDL class, there is a related lipoprotein called lipoprotein “little a,” or Lp(a) for short. The density of the particles are related to their lipid-to-protein ratio. The particles with the most lipids, like CMs and VLDLs, are larger and more buoyant (and therefore less dense) compared to particles carrying fewer lipids, like LDLs and HDLs, which are smaller and denser. I think it’s easier to understand this if you consider the information and illustration in Table 1 and Figure 2, respectively, putting the size, density, and composition of the different classes of lipoproteins into context.
Table 1. Classes and characteristics of lipoproteins.1
Lipoproteins are not only classified by their density, but laboratory techniques allow for the measurement of their apolipoproteins. While there are at least 10 classes, and several subclasses, of apolipoproteins, our focus here is on apolipoprotein B (apoB).
Figure 2. Size, density, and apolipoprotein identification of lipoproteins.
It turns out that each CM, VLDL, IDL, LDL, and Lp(a) has one, and only one, apoB per particle. This allows apoB measurement to serve as a particle concentration for these lipoproteins.2 All of the lipoproteins in Figure 2, with the exception of HDLs, carry a single copy of apoB. In other words:
Total apoB concentration = CM-apoB + VLDL-apoB + IDL-apoB + LDL-apoB + Lp(a)-apoB
Because of its extended plasma residence time, more than 90% of apoB-containing particles in plasma are LDLs, which means apoB measurement mostly represents LDL particle concentration. Overall, you can think of apoB as a collective measure of all potentially atherogenic lipoproteins including, if present, Lp(a), and this entire family of apoB-containing lipoproteins are shown in Figure 3, including VLDL and its atherogenic remnants.
Figure 3. Apolipoprotein B-containing lipoproteins.
When you get a standard lipid panel and the familiar readout of TC, LDL-C, HDL-C, and TG, it’s showing you the mass of these lipids (i.e., cholesterol, except in the case of the TG measurement) per unit volume of plasma. Here in the States, the mass is shown in milligrams and the unit volume of plasma is a deciliter (i.e., one-tenth of a liter). For example, an assay may show the mass of TGs are 100 mg/dL and the mass of cholesterol in all of the lipoproteins circulating per unit volume of plasma is 200 mg/dL. In other words, TC is the sum of all of the cholesterol within each of the distinct lipoprotein classes, as illustrated in Figure 4 and is expressed in the following equation:
TC = VLDL-C + IDL-C + LDL-C + Lp(a)-C + HDL-C
Figure 4. Lipoproteins and their cargo content.
Although LDL-C can be directly measured, LDL-C reported by most labs is usually calculated based on direct measurements of TC, HDL-C, and TG, and is called the Friedewald formula. This formula subtracts HDL-C and VLDL-C from TC to estimate LDL-C. VLDL-C is estimated as TG/5, which assumes VLDLs have 5 times more TG than cholesterol.3
Therefore LDL-C is calculated as:
Calculated LDL-C = TC – HDL-C – (TG/5)
The non-HDL-C measurement, shown in Table 2, is a metric that is increasing in popularity for predicting ASCVD risk. By subtracting HDL-C from TC, the resulting non-HDL-C is the sum of all cholesterol carried within the apoB-containing lipoproteins. Non-HDL-C measurement is to apoB measurement what direct LDL-C measurement is to LDL particle measurement.
Table 2. Commonly reported lipid concentration measurements.
So what is the upshot of this
- Cholesterol (and triglycerides) can’t just float around in our circulation since they are not water-soluble, so we need elaborate vehicles to move them around. These vehicles are called lipoproteins.
- Lipoproteins differ by many properties, but a couple stand out: their density and their apoproteins. On the one hand, we have a family of high-density lipoproteins, cloaked in apoA-I apoproteins, and on the other hand, we have a family of low-density lipoproteins, cloaked in apoB apoproteins.
- The apoB-bearing lipoproteins are the atherogenic ones, and in most people ~90% of the apoB-bearing lipoproteins are low density lipoproteins (LDLs).
- The common, or typical, lipid measurements used by most physicians (e.g., LDL-C, non-HDL-C) are simply correlates of apoB particle concentration. Importantly, these surrogates can often be misleading.
In Part 2 of this email, we’ll discuss why this discordance between apoB and its surrogates exists and why it poses a problem for anyone interested in reducing their risk of atherosclerotic heart disease.