Some friends and I were discussing ApoE today (since this is what “normal” people do to unwind on Saturdays), and since a recently published article revealed a new ApoE isoform called ApoE2 WOLVERINE (cue the “Hugh Jackman gets his lipids managed by Peter Attia jokes”), I figured it might be fun to talk about ApoE BELOW THE BRAIN in the context of Type III Dysbetalipoproteinemia (for more on ApoE in the brain, check out THIS PODCAST where I discuss this).
Although there are some rare ApoE isoforms (such as the aforementioned Wolverine, ApoE Christchurch, ApoE1, ApoE5, and ApoE7), ApoE mainly comes in 3 flavors: ApoE2, ApoE3, and ApoE4. And your APOE Genotype can be determined by a widely available commercial lab test. Since you get one APOE (Chromosome 19) from Mom and one from Dad, you can have the following APOE genotypes:
-E2/E2 (very rare, and the topic of today’s topic). Most people with E2 have lower LDL-C and lower Alzheimer’s Disease risk.
-E2/E3
-E3/E3 (most common…about ¾ of people have this one)
-E3/E4 (14% of folks have at least a copy of E4, and this is well-known as a genetic risk factor for Alzheimer’s). Folks with E4 tend to have higher LDL-C levels as well.
-E4/E4 (I call this “APOE-Thor since Chris Hemsworth has this genotype).
People who are E3/E3 have a cysteine amino acid at position 112 and an arginine at position 158. But if that cysteine 112 is swapped out for an arginine, it’s an E4, and if that arginine 158 is instead a cysteine, it’s an E2. Crazy how ONE AMINO ACID can change the entire ballgame…almost like this system is Immaculately Designed!
ApoE3 preferentially binds to small HDL particles, and 60-90% of HDL particles have ApoE, while ApoE4 preferentially binds to large VLDL particles; 35-60% of VLDL and about half of IDL particles have ApoE. LDL particles, which are the most numerous of the ApoB-100 particles under normal circumstances, almost never have ApoE.
And since ApoE means Easy Access to the liver for clearance, this is a big reason why LDL particles generally have a much longer plasma residence time (several days) vs VLDL particles (2-6 hours) and IDL particles (half hour or so).
Now here’s where it gets crazy (ok, we’re already well past the realm of normalcy, but budding Lipidologists need to hang with me here). ApoE4 is actually the PREFERRED LIGAND for the LDL receptor; if a particle has ApoE4, it tends to be rapidly recognized and taken up by the LDL receptor. Conversely, ApoE2 has INCREDIBLY POOR binding affinity for the LDL receptor.
So by now you’re probably doing something more fun, like watching NCAA Tournament Basketball or doing your taxes, but putting all these concepts together will help you understand the darling (or atheromatous stepchild) of board exams, Type III Dysbetalipoproteinemia (or Remnant Hyperlipoproteinemia).
Recall that lipoproteins carrying ApoE have Easy and Enhanced access to the liver. Most ApoB-100 lipoproteins that have ApoE are triglyceride-rich VLDL and IDL. And since VLDL and IDL particles possess FAR MORE CHOLESTEROL PER PARTICLE than LDL, the liver in ApoE4 carriers quickly satisfies its intracellular cholesterol quota. (VLDL particles typically have >7,000 molecules of cholesterol, whereas LDL particles have ~2200). Subsequently, LDL receptor expression is downregulated.
The converse is true for ApoE2 carriers; E2 is like a poorly forged fake ID that isn’t fooling anyone, so LDL receptor expression INCREASES given that the cholesterol-rich VLDL and IDL particles with ApoE2 tend to NOT be cleared as readily. Ergo, ApoE2 carriers usually have lower LDL-C…EXCEPT in rare cases where E2 homozygotes (not always, but for Board Exams, they will be E2/E2) have a “Second Hit” of insulin resistance, alcohol use, medications that impair lipoprotein lipase activity, or a combination of similar factors. In these situations, a disastrous accumulation of triglyceride-rich remnants can result in palmar xanthomas and accelerated atherosclerosis.
In this rare instance, the majority of atherogenic lipoproteins are not LDL particles; although the total cholesterol and triglycerides will be quite high, the ApoB and directly measured LDL-C will be comparably low! (The total cholesterol:ApoB ratio will be >6.2 while triglyceride:ApoB ratio will be <10).
So now I’m sure the pathophysiology of a rare lipid disorder is crystal clear, but one burning question lingers…
Why is there a seagull with hair like me drinking coffee and reading my book in the picture? My wife made it and thought it was hilarious. Happy Easter!
