Thread by @DaveKeto

1/ Thread:

***Why LDL and ApoB Shouldn't be used Interchangeably!***

I think there's a very serious problem resulting from confusion on these two markers that may appear to be exactly the same, but aren't.

Knowing the difference can explain quite a lot...

2/ First, you need to know the typical lineage of an LDL particle. How did it start out?

An LDL usually starts out as bloated with triglycerides (TGs) with a few other proteins on it and is known as a VLDL (very low density lipoprotein).

After dropping off TGs, it remodels...

3/ ... to an IDL (intermediate density lipoprotein) and then many go on to become LDL (low density lipoprotein).

Now there's one thing VLDLs, IDLs, and LDLs have in common -- they all carry with them exactly one copy of a protein called ApoB throughout their lifecycle.

4/ So in a sense, VLDL, IDL, and LDL are all "stages" in an ApoB lipoprotein* that comes from the liver.

*(Technically, some hepatic ApoB lipoproteins can start out as LDL, but we'll save that for another time)

5/ And get this, VLDL and IDL stages are extremely short compared to the LDL stage:

VLDL - 30-60 minutes
IDL - 30 minutes
LDL - 2-4 days!

Which means in a healthy metabolism, it is common to see 95%+ LDLs and far less VLDLs and IDLs.

Thus, 95%+ of ApoB are LDLs, right?

6/ Hold it! Here's where it's easy to miss the fine print.

Note I qualified "in a healthy metabolism"

What happens in an *un*healthy metabolism -- particularly one where someone is, say, hyperinsulinemic T2D?

Do we see only a tiny fraction of their ApoB as VLDL? Often we don't

7/ Let's return to our lineage again, only this time I want to overlay that important part on dropping of the TGs, because that's all a part of energy delivery to tissues.

See the dotted line? VLDL and IDL residence time is heavily influenced by the successful delivery of TGs.

8/ I have and continue to make the case that the high VLDL/IDL (and other remnants) we see in hyperinsulinemia (T2D, etc) is commonly a clear indication of metabolic dysregulation.

Simply stated, I posit this is high level energy delivery failure, and that's generally very bad.

9/ So can we just look at VLDL/IDL (as well as other remnants) *without* including LDL?

Yes -- it's already identified in the literature as "remnants".

And in fact, one can look at "remnant cholesterol" as it is far more associated with ASCVD than LDL-C.

10/ Which brings us back to the problem of looking at ApoB.

ApoB lumps in both remnants and LDL.

Given remnants have a massive association by itself without LDL -- using ApoB manages to attach LDL to the outcomes anyway so it's sure to get the blame.

11/ I'll have new data to share soon regarding ApoB when looked at with low triglycerides (and thus, low triglyceride-rich remnants).

And of course, this is very relevant to low carbers given they often have very high ApoB, yet very low triglycerides.

12/ So the tl;dr--

Remnants have a high association with ASCVD and all cause mortality.

ApoB lumps remnants and LDL together, thus creating the impression LDL has this high risk association where likely far more remnant-related.

Solution: don't use ApoB and LDL interchangeably