Tuesday, August 05, 2008

AGE RAGE and ALE: segregation

Both glucose and fructose are transported from the gut to the liver via the portal vein. I've never seen papers which have measured the concentration of either of these sugars in the portal vein, but the determinants must be rate of uptake from the gut, strongly influenced by dietary load, and splanchic blood flow, a high flow carrying the sugars at lower concentration per unit uptake. Ultimately this blood flow must carry the highest plasma glucose concentration and absolutely the highest plasma fructose concentration in the body, especially in the aftermath of drinking a giant Pepsi. Or maybe after a detox dose of Kiwi fruits.

Fatty acids come as mixtures. Even beef dripping carries a small load of PUFA. Nuts more so, seeds like those from Sunflowers much more so. Humans eat all of these in variable quantities. They are broken down by lipase, absorbed in to intestinal cells and reassembled in to triglycerides to be secreted as chylomicrons. Chylomicrons are the bulk transport system used to get lipid, including the PUFA, from the diet to the muscles, fat and the liver. A chylomicron is labled with a marker protein. It's a truncated form of that good old apoB100 used by the liver to mark the VLDLs destined to become LDL particles. The truncated protein is called apoB48. It starts life as an apoB100 but gets a socking great chunk cut off between transcription and particle assembly. It looses the LDL receptor interacting section but keeps the AGE triggered switch. No one seems to have looked at how glycation of chylomicrons acts in terms of receptor attachment to deliver lipid to muscles, or it's interaction with the "LDL-like" receptor which allows it to be recycled by the liver. I'll bet both actions get mangled by glycation. It does seem reasonable to assume that glycation allows chylomicrons to interact with RAGE, the receptor for glycated lipoproteins on mesothelial cells, in particular macrophages. These are the cells which make foam cells as part of atherosclerotic lesions.

This seems to be a feature of all apoB containing lipoproteins which have been glycoxidised. Obviously you would expect this to be a problem in the chronic hyperglycaemia of diabetes.

If your dietary carbohydrate intake stays within the capability of your liver to handle effectively, avoiding systemic hyperglycaemia, there is no need for foam cell formation. Avoiding chylomicron glycation under these physiologically normal circumstances, ie when you don't need foam cells, is likely to be beneficial. That's what happens.

The body actually puts chylomicrons in to the lymphatics which drain the gut, not in to the portal vein. They then pass down the thoracic duct and directly in to the venous circulation, avoiding the portal vein and its glycating environment. Mixing bulk lipids with bulk sugars gives bulk glycoxidation. Evolution has segregated them.

I'd always wondered why the digestive system was arranged this way. Now at least I have some idea.

Peter

10 comments:

Dave said...

Nice. The circuitous route of LCFA compared to other macronutrients always left me scratching my head. Now at least I have decent hypothesis why fat is segregated. Plays nice with a lot of other aspects of metabolism as well. Insulin activation of LPL peaks around 4 hours after initial meal-induced insulin stimulus, corresponding nicely with the peak in chylomicron concentration. The blood sugar increase from a normal carbohydrate load would be used up by this point, so the body should be transitioning back to fat burning. The segregation not only keeps postprandial glucose and lipoproteins separate in the portal vein, but also in general circulation, and tends to make only one fuel type available at a given time.

Now, if your lipoproteins are chronically elevated and you crank your blood glucose via large refined carb intake, you're asking for trouble in the form of glycation. For that matter, the chylomicron peak corresponds pretty well with our socially defined interval between meals. That means your chylos would be around max when you dumped the next load of glucose in the blood, with the consequences you've discussed. Additionally, you'd be supplying extra glucose and insulin to esterify the fat from the previous meal, promoting fat storage at a time when both chylo concentration and LPL activity are maximized. The increased LPL activity in adipose tissue leads to higher serum plasma levels of fatty acids, which in turn tend to make muscle tissue insulin resistant, cutting off one of the major depots for excess blood glucose. Net effect: increased glycation of lipoproteins, insulin resistance in muscle leading to poor glucose tolerance, and enhanced fat storage in adipocytes. Sounds like metabolic syndrome to me.

Peter said...

Hi Dave,

Yep, I'll buy that. The world is understandable, it fits together.

Peter

scott said...

MCT's, with their shortcut to circulation, would seem to confound the body's built-in partitioning of macronutrients (if the hypothesis is correct), placing more fat in circulation at a time when it could do most damage via glycation. If MCT causes the same issues as other fats. If they do...perhaps a reason to avoid concentrated MCTs such as those found in cocunut or refined MCT oil. Not enough data, probably, but worthing thinking about. Animal fat wins again

Dave said...

MCTs are an interesting issue. People often talk how they get a direct ride to the liver in the portal vein, bound to albumin. So in that scenario, I would guess the issue is different, since there's no lipoproteins to damage directly. The question is what happens next. The liver presumably uses some of the MCTs for energy (the liver prefers fat as its energy source), but does excess get esterified and trucked out via VLDL? Or is it released as NEFA again bound to albumin? I don't know, maybe somebody does.

Breast milk is high in both MCTs and sugar, so it's tempting to extrapolate that the body knows how to make these two play nice together. But neonatal metabolism may be different in some way to accomodate this situation.

mtflight said...

but aren't MCT saturated? I think the hypothesis implies that it's the PUFA content that is easily [readily] damaged.

Taka said...

Given the different timing of the sugar versus chylomicron entry into the bloodstream - would it be more protective to eat carbohydrates first and then later eat the PUFA containing fat (and then fast possibly overnight)? If the chylomicron peak 4 hours after eating a high fat meal, carbohydrates (e.g. fruits) would be a killer when consumed as the next meal. But in some nations like Japan people eat the fatty fish first and then at the end of the meal add the rice.

Peter said...

Dave, Scott and mt,

Just googled MCTs and adipose composition. Depends on your model; piglets and human neonates accumulate MCTs in adipose tissue (can't see if access is via direct FFA, VLDL with MCTs or chylomicrons with MCTs), rats don't, adult human studies suggest MCT provide ketones via the liver which get assembled as palmitic acid in adipose tissue. So you can take your choice.... Ultimately MCTs are all saturated and won't randomly oxidise anyway, so there is much less of an problem here.

Taka,

You raise a number of issue which might become clearer, but yes, having a sunflower oil based spread on your toast and peanut butter at breakfast time, then snacking on fruit a few hours later might be a worst case scenario. Do the Japanese have any major source of omega 6 PUFA in their traditional diets? White rice is essentially fat free and I've never heard of rice oil, or soya oil for that matter, as a traditional staple food. Omega 3 are a different scenario, posting soon.

Peter

Taka said...

Thanks for the comment Peter. Actually when my health was deteriorating I was drinking a "high antioxidant" but also high fructose 100% fruit & vegetable juice just 3 hours after the usual PUFA-rich lunch (instead of the afternoon tea).

As for novadays Japan people here do consume lot of Omega-6 rich soy, canola and corn oils in the form of fried items. There has been also an unrestricted use of trans-fats so far. However, at the same time they are still eating high Omega-3 fish diet supplemented with soy (tofu), green tea, ginger and other potentially protective substances. This may create a pro-apoptotic environment which could protect against cancer and possibly increase longevity through the stimulation of tissue renewal. One big difference from US and UK is that most of the drinks in vending machines are unsweetened with HFCS and people generally don't overeat.

Looking forward to your post about Omega-3. They are even more susceptible to oxidation and are trucked in the same chylomicron so as far as AGEs/ALEs are concerned they should be of even bigger concern. But at the same time they are inhibiting the inflammatory processes via arachidonic acid metabolite suppression. Perhaps the ALEs without accompanying inflammation are the "healthy" Japanese way?

Bruce K said...

"Mixing bulk lipids with bulk sugars gives bulk glycoxidation."

Esp when they are high in PUFAs, or cooked at high temperatures in open air, or cooked together (caramel or doughnuts or french fries). What is missing from this analysis is proof that carbs are the major culprit in glycation. According to this study, cooked fats and proteins are 13-29x more prone to glycation damage than carbohydrate foods, on average. The problem of AGEs should be minimized eating raw carbohydrates, fats, and proteins. Limiting PUFAs would help prevent glycation in vivo.

http://www.ncbi.nlm.nih.gov/pubmed/15281050

Michael Eades think dietary AGEs do not matter, because they're usually not absorbed efficiently. I've read conflicting opinions that diabetics absorb more AGEs from food. But the fact remains that cooked fat, meat, and PUFA oils are worse for causing glycation than carbohydrates.

Bruce K said...

"Perhaps the ALEs without accompanying inflammation are the "healthy" Japanese way?"

I think it's even better to get rid of the ALEs and the inflammation by simply "limiting all PUFAs equally" which seems to be what Ray Peat has been doing with great results. That way, you don't need to rely on fish which are highly polluted or rancid overpriced fish oils / supplements.