Why Some People with Sky-High LDL Don’t Get Heart Disease

Why do some people with crazy high LDL-C and ApoB develop no plaque in their arteries, while others – including those with far lower LDL and lower ApoB – do develop plaque?

Why do some people with crazy high LDL-C and ApoB develop no plaque in their arteries, while others – including those with far lower LDL and lower ApoB – do develop plaque?

We know this is a phenomenon. Even the staunchest pro-LDL and ApoB-lowering devotees admit… you can have high LDL and ApoB and be perfectly healthy. For example, quoting lipidologist Thomas Dayspring, “There are people with high ApoB who live long and healthy lives… But I don’t know what else is going on in their artery wall.” (From: The Drive Podcast, Episide #334, ~57:40)

So, let’s tackle one possible explanation centered around the following term: “Transcytosis.”

I know, ‘transcytosis’ sounds like a secret maneuver in a sci-fi space battle—‘Initiate Transcytosis, Captain!’

But in reality, it’s just how stuff sneaks past your artery’s security system, or - rather - is your artery’s security system.

Transcytosis, Made Simple

Your arteries are lined by cells called endothelial cells. Endo- means within, as these cells are within the tube that composes your blood vessels. A coronary plaque grows when cholesterol-containing particles, including LDL particles, slip through the endothelial barrier and begin to seed a plaque.

But HOW do cholesterol-containing particles penetrate the endothelial barrier? It’s not like a healthy endothelial barrier is coarse chicken wire. It’s rather tightly knit.

That’s where “transcytosis” comes into the picture.

Transcytosis is the process whereby a cell – in this case, the endothelial cells lining your arteries – sucks up something from outside (here, an LDL particle containing cholesterol), passes that something through its interior, and then out the other side.

By way of analogy, think of your artery wall like an exclusive nightclub. Some particles get waved in VIP-style. Others get stuck outside. But what if LDL wasn’t just passively slipping through a hole in the wall, but was actually being escorted through by a bouncer? That is - more or less - transcytosis.

Your Coronary Epiphany!

Now, given this perspective, you may have just made a connection or had a coronary epiphany!

People often talk about the process of plaque development in a manner that suggests the more cholesterol-containing particles you have in the blood, the more that end up getting inside your artery wall and getting trapped there.

Let me be clear, this idea that more cholesterol containing particles in your blood automatically equals more flow of these particles into your artery walls (and more coronary artery disease) is a MASSIVE ASSUMPTION and likely incorrect, or at least incomplete.

Instead, transcytosis is an active, regulated process – as nicely described in a new 2025 paper in the journal Atherosclerosis, Thrombosis, and Vascular Biology (ATVB).

A Deep Dive into Mechanism

This new paper describes how “transcytosis across endothelial cells is the dominant pathway” by which cholesterol-containing particles get across the endothelium and notes how this might explain “currently unexplained differences in disease susceptibility.”

Now, I want to highlight some fascinating points raised by this paper about the regulation of transcytosis. (As you read, you may want to refer to the below figure from the paper, particularly the components: LDLR, SR-B1, and ALK1 in the top right.)

LDL receptor: Inflammation Matters

First, whereas one might think the LDL receptor is key to the process of transcytosis of LDL particles across the endothelium in heart blood vessels, that’s not the case.

LDL receptors in the coronary endothelium can promote transcytosis, but particularly in an inflammatory environment when stimulated by the inflammatory signaling molecule, the cytokine, IL-1β.

Thus, the LDL receptor can promote transcytosis of LDL particles containing cholesterol into blood vessel walls, but particularly when inflammation is high.

This also suggests low inflammation will lower LDL receptor-mediated transcytosis at the coronary endothelium and reduce plaque development.

SR-B1 and the role of HDL

A more important receptor in the transcytosis of LDL particles is SR-B1. The reason this is so interesting and important is because the best-known ligand – or binding partner – for SR-B1 is HDL particles, often called the “good cholesterol” particles. That is a simplification, but higher HDL cholesterol levels are typically associated with metabolic health.

Critically, studies show HDL can compete with LDL for SR-B1 and lower LDL particle transcytosis.

So, in effect, the HDL particles can act like bouncers, preventing LDL from slipping into the club, by which I mean past the endothelium into the artery wall. And this might be one more way HDL is cardioprotective.

ALK1 and Metabolic Disease

The third receptor is called ALK1. One regulator of ALK1 is a signaling molecule called BMP9.

And BMP9 reduces ALK1 levels, thus reducing transcytosis of LDL particles. This means lower BMP9 levels would cause more LDL transcytosis and increase susceptibility to coronary artery disease.

• Question: And guess under what conditions BMP9 is low?

• Answer: Metabolic syndrome and Type 2 Diabetes.

In those with metabolic syndrome and insulin resistance, BMP9 levels are reduced, which would logically lead to more LDL transcytosis and eventual coronary plaque progression.

This may be another way insulin resistance causes coronary artery disease.

Mechanistic Summary

Putting it all together, we have three key receptors involved in transcytosis: LDL receptor, SR-B1, and ALK1.

• LDL receptor-mediated transcytosis is activated by inflammation.

• SR-B1-mediated transcytosis is inhibited by HDL particles, particularly larger HDL particles

• And ALK1-mediated transcytosis is inhibited by BMP9, which is reduced by insulin resistance.

The rest of this letter will discuss how this relates to the study of people with VERY high cholesterol, LDL-C, and ApoB on ketogenic diets. It will also direct you to further content on the complexities of cardiovascular disease, and give you a teaser of some major upcoming work. If you have the means to become a premium (paid) subscriber and support what I do and our collective Metabolic Health mission, please subscribe.