Thread by @POhukainen

🚨 Thread time! 🚨 Fascinating research *letter* (lol, contains more data than many "regular" papers combined!) published in @nature. Looks at the molecular mechanism of how #LDL #cholesterol particles get into arterial walls and cause #atherosclerosis | nature.com/articles/s4158…

The authors build upon previous knowledge that a particular scavenger receptor (SR-B1) has a key role. As the name implies, scavenger receptors pick up all sorts of stuff from their surroundings (2/14).

First, a transgenic mouse is made that has SR-B1 knocked out *specifically* from endothelial cells. This was done in combination with different athero-prone- and control mice and the data consistently shows that if there's no SR-B1, there's much less atherosclerosis (3/14)

Then, the authors zoom in into molecular detail. They look at specific mutations within that receptor protein and show that virtually all of them have the same effect: if the receptor doesn't bind to LDL particle, it doesn't get into the cell any other way, either (4/14).

They also track down an interacting protein (DOCK4) that internalises the scavenger receptor once it has picked up an LDL particle. Here, the authors show more interesting data: there's no difference in binding OXIDIZED or native LDL (5/14).

Previous fig also shows human data from three separate (small) cohorts. In them, it seems that both SR-B1 and DOCK4 are upregulated in atherosclerotic human arteries. This essentially implies that those places suck up LDL particles more readily than other parts. (6/14)

The authors also add another piece (RAC1) to the puzzle that links the binding and internalisation of LDL particles to exocytosis (together = transcytosis) (7/14)

This is truly impressive work! However, human data is very limited. For example, it would have been interesting to see SR-B1 and DOCK4 expression in various parts of the human arterial tree (athero-prone vs. non) instead of actual atherosclerotic tissue vs. healthy (8/14)

This is why I disagree with the authors' strong conclusion that this challenges the idea of passive pathways through the endothelium. In fact, there's a large body of evidence showing that athero-prone regions of human arteries are subject to strong hemodynamic forces... (9/14)

...that have disruptive effects on local endothelium: ncbi.nlm.nih.gov/pubmed/17599600

Obviously, mice have much smaller arteries and therefore smaller hemodynamic forces. IMO it could be that SR-B1 has a more pronounced effect in mouse atherosclerosis compared to humans (10/14)

But this data still has important implications to humans, as well. For example, a lot of molecular work was done in human cells and receptor constructs. No reason to believe this molecular biology would be any different in living humans (11/14)

Secondly, this is a very important clarification on a common myth especially in #cholesterol denier narratives. They often claim that LDL receptors are required for the uptake of particles into cells. They then claim that, for example, familial hypercholesterolemia (FH) caused...

...by defective LDL receptors, actually causes LESS LDL accumulation into endothelial cells thereby causing some problems. This has always been bullshit and now even more so. It's clear that LDLR's are not required for endothelial uptake (13/14)

In conclusion, we now have yet another important piece into the molecular mechanisms of atherogenesis. Practical implications are the same: make sure you have as little LDL particles in your blood and as soon as possible 😊👌🏼