Altavista put up an excellent link to an article describing an AI algorithm capable of mining pubmed abstracts and coming up with gold. The exact opposite of modern meta-analysis (repeat after me: the meta-analysis of dross is dross). And the AI algorithm could use old data to predict recent discoveries! Sadly, the university I graduated from is currently teaching final year vet students that any publication over five years old is unimportant/can be ignored. The end of science. Alt was prompted to share his gem following this link put up by Hap:
C‐reactive protein promotes atherosclerosis by increasing LDL transcytosis across endothelial cells
Which is worth thinking about (and ignoring). Unless anyone thinks that LDL transcytosis across human umbilical vein derived endothelial cells (HUVECs) in culture resembles the process of arteriosclerosis, I think we can safely ignore this aspect of the modelling in the paper. Just ask yourself how severe is venous arteriosclerosis, with or without C-reactive protein. And the cells in the model die if you expose them to anything greater than 35mg/ld LDLc! But it brings up the apoE-/- mouse, a truly fascinating subject.
The apoE-/- mouse is also a model. They develop hyperlipidaemia and rapidly progressive "arteriosclerosis". Obviously, the apoE-/- lipid particles, which lack their apoE attachment protein, work their way (using active transcytosis of course) through the endothelium of blood vessels and cause cholesterol to accumulate in the subendothelial space and... Well. It's a pretty neat evolutionary dead end, if you believe it.
The apoE-/- model tells us more than anyone could ever want to know about apoE-/- mice. I've just spent some considerable time on Pubmed and SciHub trying to find out if there is any sort of full blown apoE-/- syndrome in humans. Not apoE2/E2 etc, more like no apoE at all. Zero. Zilch. Like the mice.
No luck finding it so far.
EDIT Yay, Adam found it
Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function
No suggestion of CVD. Just shows how important adding over 1% by weight of dried (oxidised) egg yolk to the diet to generate the "model" might be!
But apoE-/- mice are interesting in their own right. They really do accumulate lipids on their arterial linings in a manner exuberant enough to make a lipidologist wet their knickers. None of this messing about with the non-lipid intimal thickening so characteristic of real human arteriosclerosis. Lipids, lots of them, just "invade" the arterial walls and stick. Right there, pretty well on the surface.
Every now and then you trip over an interesting paper, in this case about why apoE-/- mice really have vascular problems. Here's one:
TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated with Hyperlipidemia
The paper is long and complex and very, very clever. As per usual. And less than five years old.
Here is the scene-setter from the discussion
"Patients with enhanced platelet reactivity are at increased risk for cardiovascular events.4, 37–39 Enhanced platelet reactivity is associated with chronic and acute inflammation, infections, diabetes, and a number of pathophysiological states related to dyslipidemia, including atherosclerosis, diabetes, and metabolic syndrome". My italics.
The mechanism appears to be through CD36, a multifunctional scavenger-type receptor present on most cells but here they are looking at platelets:
"Previously we have linked platelet hyperreactivity in dyslipidemia to accumulation in circulation of specific oxidized phospholipids, oxPC-CD36, which activate platelets via the scavenger receptor CD36"
The "previously" citation is to:
Phosphoproteomic Analysis of Platelets Activated by Pro-Thrombotic Oxidized Phospholipids and Thrombin
which introduces us to KODA-CP, or to put it more elegantly 9-keto-12-oxo-10-dodecenoic-phosphatidyl choline. This was just one of the more effective CD36 activators of the many lipid products present in oxidised lipoproteins.
So. Hyperlipidaemia facilitates the generation of KODA-CP which activates CD36, which activates TLR2, which makes platelets super sticky.
KODA-CP must have linoleic acid or arachidonic acid as part of its parent molecule.
The platelets stick. In apoE-/- mice enough of them stick to form massive aggregates on the arterial surface that look a bit like late stage lipid infiltrated arteriosclerosis plaques. It's a model.
BTW, platelets carry apoB labeled lipoproteins, among the many physiologically appropriate contents of their cytoplasmic granules (link below). Under the more normal generation of arterial intimal hyperplasia which precedes pathology I consider this lipid will simply be used for normal repair/hyperplasia processes. But there is nothing physiological about apoE-/- mice. They look like they should stick a ton of platelets to any damaged vascular wall, with more apoB labels than any-(mouse)-body knows what to do with. Given enough omega 6 PUFA to generate the KODA-CP.
Apart from the cardiologist derived omega 6 PUFA (another link below), did you notice the core involvement of the CD36 receptor? CD36 also facilitates free fatty acid uptake in to many cells. It is stored within cells and translocates to the cell surface, a bit like GLUT4 proteins, when needed. Stored in the cell, translocated when needed.
What controls CD36 translocation to the cell surface?
Insulin, of course (another post there).
Just thought you might like to know.
Let's just summarise. Lacking the apoE protein limits the utilisation of lipoproteins, much as having a fully non functional LDL receptor does in familial hypercholesterolaemia. This increases the concentration of lipoprotein particles in the circulation.
Applying the Dunning-Kruger effect to lipidology: Lots of LDLc particles = lots of invasion. QED. That's been it for the last 50 years. I don't thing many lipidologists every get past this obvious, unarguable, simple fallacy. Oh, also core to lipid "therapy" has been, and still is, giving corn oil to lower the LDLc count.
In reality the elevated lipoproteins are a marker of reduced utilisation and are associated with an increased residency time in the circulation. Given lipids based on palmitic, stearic or oleic acids I don't think that would matter.
Given lipids filled with linoleic acid, the essential precursor of KODA-CP, you will get a progressive rise in KODA-CP associated with increasing persistence of the lipoproteins. The more KODA-CP the more activation of platelets via CD36/TLR2 (and undoubtedly other pathways) and the stickier the platelets become.
Given the pathological intake of linoleic acid promoted by cardiologists and lipidologists working under their cholesterophobic hypothesis it seems perfectly possible that seed oils (and insulin) may well be drivers of the platelet adhesion which is core to the vascular damage in apoE-/- mice. Platelets even carry apoB100 labeled lipoproteins in their cytoplasmic granules which allows us to immuno-stain lipid accumulations with this LDLc implicating flag.
Given lipoproteins which lack apoE on their surface, accumulation of KODA-CP, hyperreactive platelets and a surfeit of insulin we are in a position to understand how the apoE-/- mouse works. Which is cool for those of us who like to understand things.
How much of this applies to actual human arteriosclerosis? Increasing platelet stickiness will amplify the normal response to arterial injury. I think this may be real. The rest is just a very extreme, rather bad model.
Most models, like this one, are usually useless.
Is it conceivable that cardiological dietary advice represents the exact opposite of the correct approach? That it would actively worsen the problem it is aiming to ameliorate?
Yep. But we knew that anyway.
Increasing linoleic acid in the diet is undoubtedly a facilitator of the generation of KODA-CP and the activation of the subsequent cascade goes a long way to explain the Sydney Diet Heart Study and the Minnesota Coronary Experiment. People died. From corn oil.
I'll stop now.
Some helpful links that didn't integrate neatly in to the text.
Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man (1980, written on papyrus)
Apolipoprotein B release from activated human platelets (1986, probably on parchment, safe to ignore).