Cholesterol Code

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This week, Peter Attia released Measuring cardiovascular disease risk and the importance of apoB on his blog. I think it’s well worth the read and highly encourage you to finish it first before reading the rest of this article.

One quote in particular sums the article up well:

While I have historically used LDL-P and apoB metrics somewhat interchangeably, one advantage of measuring apoB over LDL-P is that apoB encompasses all of the potentially atherogenic particles: not just LDLs, but VLDLs, Lp(a), IDLs, and potentially chylomicrons. And this point has me relying more and more heavily on apoB today than on LDL-P in my patients and myself.

Understanding Remnants

Generally speaking, particles that are neither LDL nor HDL are considered “remnants” in the literature. (There’s some further distinction regarding Lp(a) and fully lipidated Chylomicrons in rare circumstance regarding this topic, but we’ll cover that in future article).

In other words, we have three categories of lipoproteins as labeled:

• HDL particles (HDL-P)
• LDL particles (LDL-P)
• Remnants (all non-LDL-P, non-HDL-P particles)

Here’s a good summation from Wikipedia regarding Remnant cholesterol:

Remnant cholesterol, also known as remnant lipoprotein, is a very atherogenic lipoprotein composed primarily of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). Stated another way, remnant cholesterol is all plasma cholesterol that is not LDL cholesterol or HDL cholesterol, which are triglyceride-rich lipoproteins. Nonetheless, remnant cholesterol is primarily chylomicron and VLDL from which most triglyceride has been removed, such that each remnant particle contains about 40 times more cholesterol than LDL.

(Emphasis mine)

Which Lipoproteins have ApoB?

So which lipoproteins have this ApoB we’re talking about? That’s easy – basically every lipoprotein that isn’t an HDL*.

• HDL particles (has no ApoB)
• LDL particles (has ApoB)
• Remnants (has ApoB)

* [If you want get technical, there’s some differences in opinion in the inclusion/exclusion of lipid-rich chylomicrons and Lp(a), with most leaning toward exclusion.]

I actually wrote an article on remnants two years ago and included it in my presentation at Low Carb Breckenridge a few months later.

Many people (myself included, originally) used LDL-P and ApoB interchangeably given the vast majority of “ApoB-containing Lipoproteins” in our bloodstream at any given time was likely to be LDL particles (LDL-P). My opinion on this definitely changed the more the Lipid Energy Model developed, because I could see how remnants uniquely told a story of the problem that LDL particles could not.

A Simple Boat Analogy

Imagine a fleet of cargo ships that are constantly being deployed and have two jobs:

1. Deliver goods, which takes 1 hour
2. Patrol and help out, which they do for 72 hours

You wouldn’t be surprised to see about 1 in 73 of these cargo ships having cargo and the rest being generally empty at any given time. Maybe some timing on launch or deliveries offsets this slightly so it’s more like 1 in 50 at times, or 1 in 100 other times.

Now let’s change it. What if you’re not seeing just one cargo ship full of cargo, you see 5. What does that mean?

You investigate further and find that there’s a reduced ability of these ships to deliver their cargo. They’re having a hard time completing their first job — the same job that should’ve been easy and take much less time on turnaround.

Maybe there’s a problem with the docks or rockier waters or the boats themselves. Regardless, you see more boats with cargo undelivered seems to associate with bad outcomes so you start to take notice.

Yet conversely, you notice that no matter how many more total boats you have, there seems to be very few bad outcomes when at any given time there are very few that have cargo — suggesting they are making their deliveries properly.

ApoB “Boats” Failing to Deliver

Most ApoB-containing Lipoproteins like chylomicrons and VLDL have a first job: to deliver their fat-based energy (triglycerides) to cells, and in normal circumstances it should happen very quickly (typically less than an hour). Then a large portion of VLDL will ultimately remodel to LDL particles and remain in the bloodstream for 2-4 days.

So let’s recreate our boat job list from above:

1. Deliver triglycerides, which typically takes less than an hour
2. Remain in the bloodstream (potentially immune/repair) for 2-4 days

But what do we commonly see in those who are obese, Type 2 Diabetic, or suffering other metabolic derangements?

• High fasting VLDL
• High fasting Triglycerides
• And thus, high overall remnants

I posit the simple explanation in most of these cases is that there is a clearly reduced capability on the part of the existing VLDLs to make their deliveries (job #1), which matches up well with one being past the “personal fat threshold“. There’s little parking left for the triglycerides, so we see an accumulation of fat in tissues that aren’t designed to store it, such as ectopic fat.

This from a great paper that illustrates this dynamic well:

Visceral fat is considered by many to behave as an ectopic fat depot, accumulating triglycerides (TG’s) when body fat storage needs exceed the capacity of subcutaneous fat depots to function normally 

Talking LDL-P and ApoB with Attia

For those who managed to make it through the 3.5 hour podcast Peter and I had, you’ll note I kept bringing up this context often when I was outlining my dream request list on data. Peter was seeking to be helpful in talking about what datsets might have what I was looking for.

Here’s Peter:

The Quebec Heart Study, here I printed it up here. I mean, basically it’s showing it has nothing to do with the LDLC once you know the ApoB. Look at the risk.

After some further back-and-forth I managed to clarify better:

Triglycerides, HDL, and preferably LDLP. Now, there is an important distinction we’ve gotta make with ApoB, because ApoB can, in theory, also include remnant lipoproteins.

Peter agreeing on that note for what I’m looking for:

Yeah, LDL-P is more accurate than ApoB.

[Full transcript of this portion of the podcast can be found here]

Thus far, I haven’t gotten ahold of dataset where I can do that stratification, but I certainly appreciate Peter’s interest in talking about it and his consideration in helping out. (An additional aside to Peter’s credit, he further offered to cover a visit to a National Lipid Association conference where I could’ve met with lipidologists on this very topic).

Are LDLs Getting the Blame for Remnants When Viewing only ApoB?

If one has high triglycerides, one almost certainly has high remnants, given they are triglyceride rich — much more so than LDL particles.

And given high triglycerides typically result in lower HDL (that’s a mechanistic discussion for another day), it’s understandable why this dysregulation would further associate with ectopic fat and yes, cardiovascular disease. (This profile is already recognized in the literature as Atherogenic Dyslipidemia)

Which brings us right back to the “Low Carb Cholesterol Challenge“. I believe the reason we’re having trouble finding studies where high LDL is shown to be atherogenic where HDL is high and TG low is that we are seeing low overall remnants, suggesting a more optimal lipid metabolism. One that is likely functioning well by comparison to one with low HDL and high triglycerides. (To date, we still haven’t had the challenge met.)

Moreover, it makes a lot of sense why one could have higher LDL due to longer residence time of remnants — thus having a higher marginal LDL for a negative reason. The tip off for whether this is the case being high VLDL and triglycerides. But this too is a hypothesis that I’m actively testing.

Final Thought

My larger point is that it is certainly my expectation that looking at ApoB by itself would likely show a greater association with cardiovascular disease given it lumps LDL-P with remnants. But I likewise expect we’d see a much stronger association with cardiovascular disease when looking at remnants without LDL-P.

…Addendum

I realized after posting this that I oddly forgot to mention the LMHR Measurement Project and how our current efforts will actually test the very hypothesis I mention above. Shame on me!

Yes, if you — like me — would want to see if those with very high LDL-P and ApoB would see greater cardiovascular risk at a population level in spite of having low remnants and triglycerides, considering contributing to the project as we’re getting closer to reaching our funding goal. Thanks!