Tuesday, July 08, 2008

AGE, RAGE and ALE: The ALE of LDL

I looked at glucose reacting with amino groups of proteins in the last post on the formation of AGEs. Apart from protein, cell membranes and the surface membrane of lipoprotein particles contain lipids. These form the classical lipid bilayer of biological membranes. The lipids of the bilayer come in a mix of saturates, mono unsaturates and PUFA. The exact mix of saturates to monounsaturates is largely determined by stearoyl-CoA desaturase, the enzyme which puts double bonds in to saturated fats to give monounsaturates.

Interestingly this enzyme appears to be under the control of insulin and activity goes up in insulin resistant states. That's another subject.

The PUFA composition is largely diet determined.

While boiling sugar with butter gives toffee, the situation in vivo seems more complicated and the initial generation of damaged lipids (ALEs, advanced lipoxidation end products) seems to involve an amino group. These are freely available from molecules like phosphatidylserine in cell (or lipoprotein) membranes. They provide the nitrogen for the formation of that horrible unstable Schiff base and its subsequent decay. The decaying base triggers oxidation/reduction reactions which hit double bonds in surrounding fatty acids, leading to ALE formation.

There's a good summary in this paper.

I just loved the chemistry in the introduction with stuff about electron spins, the pi antibonding level and other stuff that sounds really fancy. I think it means that molecular oxygen leaves PUFA alone without a transition metal or a pre formed free radical to get things going.

Until you add glucose that is.

Now I have two complaints about this paper. First is that some of the glucose concentrations used would make the ADA blanche. Not even an ADA diabetologist would suggest a blood glucose of 500mM (ie 500mmol/l). The 200mM used to oxidise the LDL particles would have had an intact human being in hyperglycaemic coma too. This is aggressive corner cutting on a time basis I guess. They did do some work down at 5mM.

Second is that they thanked Scott Grundy for helpful discussions. If you don't know who Scott Grundy is then you haven't read enough about the cholesterol con. Big black mark to the paper.

Third is that they used oleic acid for a lot of the work. They do comment that PUFA are 10-30 fold more oxidisable than oleic acid but PUFA didn't fit their protocols. They also forgot to mention that saturated fats just won't randomly oxidise at all in biological systems. No double bonds. But who would expect that sort of information from a cardiologist?

Did I say two complaints? Fourth...

So this paper is a bit rocky.

But what I do like about it is that it appears to show that glycation is what converts an LDL cholesterol particle in to an oxLDL particle. They're not the same. This is compatible with the recent study using low fat diets to (accidentally) raise the levels of oxLDL in intact humans.

Seems like sugar is what oxidises the PUFA in LDL to give oxLDL.

Avoid sugar, PUFA or both. Seems sensible to me.

Peter

17 comments:

scott said...

I know that you eat starch and avoid most fructose. On routine days I regularly do without any starch/sugar and feel great in total ketosis.

But I have found that I must have a potato or two after an intense weight workout or sprint session or my mood nosedives and I simply can't recover for days. And I like working out, and weights/sprints are supposed to be good for insulin sensitivity, muscle mass maintenance, etc. But gotta have the starch=glucose to do it. Catch-22?

Or...a matter of degree? I assume the body can handle a certain amount of glucose and AGE's, especially if most incoming glucose is replenishing glycogen rather than floating around unoccupied and causing trouble. Best to avoid the fructose, of course.

I practice daily IF of 18-20 hours, supposed to help insulin sensitivity, too (and I have found that I just like not having to scrounge for food in the morning). So the incoming glucose may cause some AGE's but at least the insulin damage is limited.

Trade off's I guess. A diet that is much reduced glucose-wise, from the SAD, but has a few spikes a week after taking some exercise, which is good for you.

So much to sort out. The low-carb dogma had me believing that potatos were white death for years, in the same category as Wonder Bread. But over time I had to give up exercise since it wiped me out. Now I learn that potatos (in moderation) can be helpful and not all that harmful and I can lift weights again. So thanks for that, I appreciate it. But still questions linger.

My dad has Parkinsons and my family is prone to cancers over the age of 60 so I want to do the best I can in all health areas. I have slowly dropped several other blogs since I found yours. I just got tired of the paleo sites that push massive amounts of vegetables and fruit every day. So now I'm enjoying 85% chocolate, among other fatty treats and feeling very good. Thanks for the time that you put into this effort.

Scott

IWFC0dN7oN.NyycUvuSp2UfBTUwR_Fo- said...

Gentlemen -

Fiber is defined as a carbohydrate under Nutrition Facts sections of food. Should we apply fiber grams toward our carbohydrate counts if we are keeping track of P/F/C ratios, or not count them as some folks do?

Bruce K said...

Scott, I use raw unheated honey for carbs. Comb honey is the best kind, but also the most expensive. I will pay like $8 for a 16 oz box of comb honey in the health store. Mostly I use orange blossom honey, but I get it only from beekeepers who say the honey is produced without any heat. Fresh honey is more convenient than potatoes IMO and probably healthier if you get truly unprocessed honey.

I do interval training based on the writings of Clarence Bass's and Art DeVany. Ex: run up stairs, and walk down; jump as high as you can until exhaustion, hill sprints, etc. That will get you in shape fast, as will eating low PUFAs and plenty of SFAs and MUFAs. (Beef, butter, ghee, mac nut oil, 76 degree coconut oil, and cocoa butter.) I stopped eating 85% chocolate, because I think it's too high in fiber (7.5g in a 100g bar). My diet has 0-5 g of fiber.

Peter said...

Thanks for the comments Scott.

Re exercise; my wife is a Pilates enthusiast. We always make sure she has a decent glycogen load on board either from the evening before or the meal immediately preceding the session. Without it she develops muscle cramps during the class.

The whole concern about insulin takes on a slightly more benign aspect if the carb load is small/moderate and associated with exercise... It is anabolic and a decent muscle mass seems worth having.

Peter

Peter said...

iwfc,

Personally I avoid fiber almost as much as Bruce does. By the time you are under 5g/d it gets lost in the biological variation in the carb load of a given weight of food. Not all 50g spuds have exactly the same carb or fiber contents. Just avoid fiber and the calculation becomes unimportant!

Peter

marco said...

Hi Bruce.
Are you ok with 40% fructose in honey?

Marco

Peter said...

Scott,

Did you see the work on ketogenic diets and Parkinsons? Posted under Parkinsons. The message I take from this response is that Parkinsons, like Alzheimers is strongly influenced by the carb intake of an insulin resistant person. Real food LC looks the best way to avoid... Guess you're thinking that way anyway?

Peter

Bruce K said...

Potatoes have about 0.9-2.0% fiber, if the peel is removed. The average is about 1.5% fiber by weight. Dark chocolate has 7.5% fiber by weight, quite a difference. Most fruits are also low in fiber, like 1-3% range.

Marco, I don't worry about fructose in natural foods. The bigger issue is getting food that's unprocessed, with little or no additives. Amount of fructose in honey varies greatly from one variety to another, so the 40% figure is probably from clover, the most common variety. Also honey is 20% water and sweeter than other sugars, so the amount you eat would be less and the amount of sugar you take in would be less.

Peter said...

Hi Peter (and Bruce)-
What are your guys' thoughts on the merits of Red Palm Oil? On the one hand it isn't exactly low-PUFA at 11%, but on the other it is a great source of tocotrienols and tocopherols. Does the vitamin E outweigh the PUFA in terms of the effect on lipid peroxidation, or is RPO best left off the menu?

Peter N said...

Apologies for the confusion that might result from my poor choice of name in the above comment. I'm another peter, not the main man.

Bruce K said...

Red palm oil has a strong taste and many people probably won't like it. I've tried it with different foods, and been unable to find anything it goes well with. I think it might be better if you lived in an area that sold fresh palm fruit. They're oily fruits like avocados and probably a lot more better because of its high levels of carotenoids, tocopherols, and tocotrienols. But the taste for most of the oils is awful.

Peter said...

Hi Peter,

I'll take Bruce's word for that one, my food is mostly sourced around UK basic foodstuffs. That's coupled with an outlook that antioxidants are a patch placed on a pro oxidant diet. I haven't read the Shutes' work on vitamin E but I can see how it would have had an effect within the context of their patients. You need vitamin E if your lipids are made of unstable fats....

Peter

gallier2 said...

My wife's from Gabon and she uses red palm oil only for few dishes. It's called nyembwe (or something like that) and is used for a heavy gravies or for mashed cassava leaves . I do actually like the tastes of these dishes but as there are variants with other ingredients (odika and peanut paste) that taste even better, we do not use red palm oil very much.

Peter N said...

Thanks guys. Yeah, it doesn't taste great, but it provides the full spectrum of E, which seems important to me for protecting against damage from PUFA that may already be assimilated into one's cells. And, similarly to coconut oil, it's stable room temp, so I'll take that as a sign that it isn't too pro-oxidant. They carry it here in northern CA, so I'll try it as a supplement. Peter, thanks for directing me to the Shutes.

Cristian Stremiz said...

Unsaturated Long-Chain Fatty Acids induce the Respiratory Burst of human neutrophils and monocytes in whole blood

Nutrition & Metabolism
Bjoern Juettner, Janina Kroeplin, Sina M Coldewey, Lars Witt, Wilhelm A Osthaus, Christian Weilbach and Dirk Scheinichen

Background: It is increasingly recognized that infectious complications in patients treated with total parenteral nutrition (TPN) may be caused by altered immune responses. Neutrophils and monocytes are the first line of defence against bacterial and fungal infection through superoxide anion production during the respiratory burst. To characterize the impact of three different types of lipid solutions that are applied as part of TPN formulations, we investigated the unstimulated respiratory burst activation of neutrophils and monocytes in whole blood.

Methods: Whole blood samples were incubated with LCT (Intralipid(R)), LCT/MCT (Lipofundin(R)) and LCT-MUFA (ClinOleic(R)) in three concentrations (0.06, 0.3 and 0.6 mg ml-1) for time periods up to one hour. Hydrogen peroxide production during the respiratory burst of neutrophils and monocytes was measured by flow cytometry.

Results: LCT and LCT-MUFA induced a hydrogen peroxide production in neutrophils and monocytes without presence of a physiological stimulus in contrast to LCT/MCT. Conclusions: We concluded that parenteral nutrition containing unsaturated oleic (C18:1) and linoleic (C18:2) acid can induce respiratory burst of neutrophils and monocytes, resulting in an elevated risk of tissue damage by the uncontrolled production of reactive oxygen species. Contradictory observations reported in previous studies may in part be the result of different methods used to determine hydrogen peroxide production.

Nicola said...

Peter, what have muscle cramps got to do with glycogen?

A high fat diet should allow a natural approach to exercise - carb-up to exercise out again...healthy?

Nicola

Peter said...

Hi Nicola,

Pilates is a largely isometric or slow movement form of exercise, which requires enormous sustained effort form various muscle groups, at least as my wife does it in her class. During periods of sustained high muscle tension there is no facility to perfuse the muscle body. If the pressure within the muscle or its facial compartment is in excess of systolic blood pressure, it will act as a Starling valve on the arterial vessels and occlude them. Under these conditions there is no facility to supply oxygen molecules to accept electrons at the end of the respiratory chain and metabolism must be anaerobic with lactic acid generation. Neither FFAs or ketones can do anything with an obstructed respiratory chain. So the fall back is glycogen for anaerobic metabolism giving lactic acid. Chris will know better than I, but lactate generation is generally considered to be a Good Thing in terms of muscle building per unit time spent on it.

As we both run with minimal glycogen reserves, having some muscle glycogen on board does not seem unreasonable when deliberately approaching sustained anaerobic exercise conditions. I don't view 30g of carbs in a portion of chips as carb loading, particularly if we have been slacking and dropped our general carb intake down to around 30g/d, which does happen.

For myself, when I get the time for serious exercise it is hill climbing on my bike, which borders on anaerobic but I keep the work tempo to within the limits imposed by my cardiorespiratory system to supply oxygen for aerobic metabolism. Obviously it's never sustained isometric exercise. No carb load at all for this.

Horse for courses...

Peter