AGE RAGE and ALE: linoleic acid

I'm really sorry about this but I haven't quite finished with figure 1 of the engrossing commentary by Krauss. Let's open it up again here.

Now the first question we have to ask is "What is the most abundant polyunsaturated fatty acid in human LDL particles?"

OK, that's a give away at linoleic acid, our least favourite omega 6 fatty acid. This is pretty obviously the case as we've just discussed how, if you get enough omega 3 fatty acid in to a nascent LDL particle, it becomes a stillborn VLDL particle and leaves it's lipid, along with its apoB protein, in the liver. Linoleic acid based VLDLs get secreted.

So here's the tricky question. Where, in Krauss' diagram, is the linoleic acid? Well it has to be in the liver cell somewhere to get put in to the LDL particles. Clearly some lipid is added to the initial assembly of the nascent LDL, over on the left hand side of the diagram. The rest comes from that lipid droplet in the middle. You would expect that lipid droplet to be mostly saturated fat if it was fructose or alcohol derived, but with the amount of linoleic acid in the modern diet there could easily be plenty of this throughout the liver cell lipid stores.

Why is there linoleic acid throughout the liver? The liver likes linoleic acid! In an utterly artificial model, the cholesterol fed hamster (you'd better believe it!) on moderate fat diets (45% of calories from fat) show an upregulation of the LDL receptor as the proportion of fat from linoleic acid rises. Dietary saturated fat down regulates the receptor. It seems that this holds true across species and it certainly seems to work in humans, diets high in omega 6 PUFA were the classical cholesterol lowering approach pre statins. You can see why the liver should ignore an LDL particle full of saturated fat. This is Krauss' large fluffy non atherogenic lipid, used for delivering calories and cholesterol to wherever they are needed. It came from the liver, why should it go back? But why is the liver so keen to uptake LDL particles when the diet is high in linoleic acid? My guess is that linoleic acid loaded anything is a novel phenomenon and in pre agriculture times linoleic acid was probably very useful and in very short supply, so it got recycled. It is the preferred fatty acid for LDL cholesterol because, in small amounts, it has significant uses and benefits which are not provided by the omega 3 fats. So there is some logic to aborting an LDL particle over-endowed with omega 3 fats. But what were positive benefits when linoleic acid was in short supply have gone awry as the amount in the diet has skyrocketed over the last 10,000 years, especially the last hundred years or so. The knock on effects of a high linoleic acid diet are interesting for atheroma formation.

Stephan also has some interesting thoughts on linoleic acid and violence up on his blog at the moment. The two problems are interesting as while CVD mortality is currently dropping in the USA and UK, the incidence of CV disease is probably static, and might be increasing if it weren't for the decline in smoking. The fact that mortality from gunshots is rising while mortality from heart disease is falling, despite the rise in incidence for both, is a plus mark for cardiologists managing established heart problems. Trauma management has some catching up to do. Or maybe we could just give up eating 10% or so of our calories from those omega 6 fats!

Peter