Tuesday, September 02, 2008

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!



Thackray said...

Peter, All

Here is an interesting two part article about the origins and movement of omega 6 and omega 3 in plants.

The first part here: http://newsletter.vitalchoice.com/e_article000906373.cfm?x=b8drcdL,b5PRNLJ0,w is pretty basic for any reader of this blog. But the second part here:
http://newsletter.vitalchoice.com/e_article000951878.cfm?x=b8drcdL,b5PRNLJ0,w discusses plant physiology that I was not aware of.

Could there be a seasonal variation in our requirement for omega 6 and omega 3 fatty acids?

Philip Thackray

mtflight said...

Peter, this is very interesting to me.

increased linoleic acid results in upregulation of the LDL receptor... makes sense as the AHA was stamping the seal of approval on corn oil and the such.

Originally I thought all PUFAs in the liver resulted in PERPP, due to their unstable nature. So would it be safe to guess linoleic acid-derived LDLs the readily oxidized kind (PUFA status)?

Rhetorical questions:

Does a high fat, low carb diet result in large LDL regardless of fat type (sat, mono, poly, trans)?

or is it only high saturated fat that results in large LDL? (Krauss' illustration seems to indicate it's only sat fat).

We know a high carb diet results in high triglyceride output (high VLDL output?).. but how about a low carb diet very high in linoleic acid and very low in saturated fat (think "vegetarian" approach to low-carb)? I have a feeling low triglyceride output... what about LDL size and oxidation?

Anonymous said...

"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."

I believe the body is trying to get rid of omega-6 and omega-3, as fast as it can. That's the impression I got from Modern Nutrition in Health and Disease, a graduate level text.
Chris Masterjohn initially disputed my theory, but then admitted he was wrong and it seems like the body is trying to burn up PUFAs and get rid of them rapidly.

A study recently posted here offers more evidence confirming my theory. When rats are fasted intermittently they burn off 81% of the omega-6 in their diets and 89% of the omega-3. When they're not fasted, they still burn up 66% and 78% respectively. I wonder why the body would burn them up even faster after being deprived of these "essential fatty acids" on a fast. Could it be because they're not essential at all, nor are their derivatives (AA and DHA)?

Anonymous said...

It should be noted that the study I mentioned only fed rats 3% calories as linoleic acid and 0.15% calories as alpha-linolenic acid. I bet most Westerners eat more LA than just 3% of calories, as do most low-carbers probably. 3% PUFAs is pretty low in caloric terms and still the rats in the study were burning the PUFAs up like crazy to get rid of them. It's hard to see how the dogma of PUFA's essentiality ever got started, when PUFAs are toxic at high levels, and the body wastes them at low levels, even after temporary deprivation by fasting. I don't see any way to get around these facts, except to think that PUFAs are toxic, and we should eat as little as possible. Also not eating 3-6 meals a day seems like a good idea with precedent.

Puddleg said...

Why does omega 6 increase LDL-R expression? Easy!
The more PUFA is taken up by cells the more fluid their membranes become. This threatens cell stability. The cell walls need reinforcing. What is the standard stiffener? Cholesterol.
On a high PUFA diet, cholesterol synthesis and uptake are increased while serum levels drop.