Saturday, March 06, 2010

Lipoprotein(a) and tissue transglutaminase

"Lp(a) levels are low at birth and rise significantly between 0 and 7 days post partum; in this newborn population, a continuous rise of the mean Lp(a) levels was observed until 180 days"

Well, that's it. The smoking gun of arteriosclerosis. As we know, arteriosclerosis is essentially non existent for humans in-utero and it starts soon after birth (in the 1950s anyway, we may do better at damaging unborn children nowadays). Lp(a) starts low at birth and rises soon after. You only need to be a cardiologist to see the obvious cause and effect here.

OMG it must be so embarrassing to realise that LDL-C has nothing to do with the process, it's been that nasty Lp(a) all the time!

So the obvious explanation must be that Lp(a) worms its way through the arterial endothelium and rips and tears the elastin fibres of the intima to shreds. Simple and utterly plausible. Probably carries a flick-knife.

Except for the tissue transglutaminase (TTG) issue.

We have all heard of this enzyme as an antibody-ligand when testing for coeliac disease, but what does TTG actually do?

Well there is an awful lot of information in this paper. This is what they looked at:

"Because of its intimate interaction with fibrin and/or cell surface oriented structures, we asked whether Lp(a) could be a substrate for transglutaminases (e.g. Factor XIII, tissue transglutaminase). These enzymes catalyze cross-linking between endo-gamma-glutaminyl and endo-epsilon-lysyl residues of proteins (16) resulting in irreversible homo or heteropolymerization of susceptible proteins."

Note the heteropolymerization. Hetero means mixed. If TTG really acts on Lp(a), it doesn't just bind it to more Lp(a), it will bind it to other TTG substrate proteins too. Many of the other TTG substrates are physically part of the cement between cells. Molecules like fibronectin.

"First, substrate specificity was compared with known transglutaminase substrates including fibronectin (17) and alpha 2-plasmin inhibitor (30) and substrates of poor or unknown transglutaminase susceptibility including IgG, alpha 1-proteinase inhibitor, and albumin. This showed that Lp(a) had amine acceptor qualities comparable to that of fibronectin and alpha 2-plasmin inhibitor where as IgG, alpha 1-proteinase inhibitor and albumin failed to incorporate significant amounts of DSC."

So Lp(a) will heteropolymerise with fibronectin:

"FXIII or tissue transglutaminase may catalyze cross-linking and deposition of Lp(a) to surface oriented structures (e.g. connective tissue matrix proteins) and/or cell surfaces."

If you are wondering what fibronectin really does, from wiki:

"fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans" (as well as intergins). Oh, look, proteoglycans...

And integrins, from wiki:

"Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the extracellular matrix (ECM). They also play a role in cell signaling and thereby define cellular shape, mobility, and regulate the cell cycle."

So TTG binds Lp(a), almost certainly to fibronectin, one the main proteins which glue our tissues together. Lp(a) is not randomly sticky. It is enzymatically and specifically integrated in to the matrix of exposed extracellular material in the wall of a damaged artery.

If we reject the hypothesis that Lp(a) circulates with an elastin-targeted flick-knife in its pocket, we can look at the specific and deliberate incorporation of Lp(a) in to a cross-linked network of tissue proteins. This looks like an emergency repair kit to me. Elastin is broken by mechanical stress. Birth, growth, pulsation of arteries, hypertension, relative movement of the supply artery against fixed arteries like the intercostals, branch points in arteries etc are all mechanical stressors. Broken elastin implies stretching of the artery beyond what the elastin will tolerate. Damage to the elastin comes with damage to the endothelium. Disrupted endothelium exposes extracellular matrix and needs a clot to patch it and the clot needs strengthening. An area of damage intrinsically means that the location was too weak. Adding some fibrous tissue and a stronger muscle around damage is an adaptive stratagem in an injury-disrupted provenly-weak arterial area.

Looking at Lp(a) as a repair kit you can make certain predictions, especially if the repair kit is rather helpful.

First is that not having any Lp(a) is bad. Well, we know that's the case.

Next is that having some Lp(a) is good, we know that too from the same graph.

If you are genetically well endowed (with repair kits) they will not show up as repair patches on your arterial wall unless you are actively damaging that arterial wall. ie High Lp(a), (genetic low kringle IV repeat numbers) means nothing if you are not damaging your arteries. Thanks to Kurt for that anecdote!

If you do lots of damage, you will need lots of repair kits. Lp(a) goes up with carb intake and down with saturated fat intake. Check DELTA.

EDIT: Also from DELTA, your body anticipates damage, or detects actual damage, if you replace the saturated fat of the SAD with monounsaturated fat. So it makes more Lp(a). That's it. You liver is worried by MUFA. Extra virgin olive oil is heart healthy? Dump it for lard or, better still, beef dripping! Less plant antioxidants for your liver to eliminate too.

If you do some thing stupid, like pushing your carb intake beyond what is acceptable (even as a non industrialised form of carbs), your liver will make extra repair kits and they will be both needed and used on your arteries. Remember the vegetarian Bantu farmers getting nearly 90% of their calories from complex carbohydrate? Blood pressure rises with age. Not so at 70% from carbs in the Bantu fishermen.

The more damage, the more repair kits get made, the more repair kits get used. The more damage, the more blood pressure rises with age.

Lp(a) rises soon after birth because birth is when pressure induced damage starts. Life, especially being born, is a damaging process. Some lives are more damaging than others.

Are you going to blame the rising blood pressure on the repair kits? Have you forgotten to take your statin today? You may also have forgotten where you left your blood pressure tablets.


BTW, obviously these stable fibrous arteriosclerotic lesions have nothing to do with heart attacks. Heart attacks happen in the elderly, not in infants!


Jacqueline said...

And not forgetting the changes in the newborn's vasculature that take place after birth: closure of the foramen ovale and withering of the ductus arteriosus. That must require some serious construction work. No wonder Lp(a) rises so steeply in the first week.

donny said...
The young rabbits were far more susceptible to cholesterol-induced atherosclerosis than older
animals and these changes were accompanied by loss of EDR. In the older animals the loss of the
latter property was not accompanied by a significant degree of atherosclerosis although hypercholesterolaemia
was present

How many rabbits have to die before people start taking this stuff seriously?

I saw a hedgehog at the cottage last summer. I hadn't realized how slow they are. What does this say about their metabolism? Maybe their form of lp(a) is made necessary by this?

Just a tiny bit of abstract here;
In the lethargic hedgehog, blood glucose regulation seems effected without insulin intervention since hyperinsulinaemia or insulin antiserum injection did not alter blood glucose during 24 hr.
According to this, it's hard to do mucopolysaccharide without insulin;

Maybe lp(a) is a smoking gun for species that ought, at least periodically, to be in a fairly low-insulin state?

Sorry I couldn't think of anything to say about serotonin. :)

donny said...

Or at least in a non-pathological insulin-resistant state. This fits in pretty well with Dr Davis' recent description of the typical high lp(a) male;

"Slender--Sometimes absurdly so: BMIs of 21-23 are not uncommon. These are the people who claim they can't gain weight."

Winalot said...

I always thought being an ultra-lean chap with veins on his abs and was good, but now I read I'm probably a typical high lp(a) male I guess it's bad?

Or as I'm powered by SF, in ketosis, have physiological IR, low BMI, lean muscle mass I'm good to go (or at least doing the best I can to live longer)?

Peter said...

Yes Jacqueline, there's a lot happening on the remodelling front!

Interesting donny. Of course one of the better kept secrets in cardiovascular research is that certainly rats and rabbits all develop "ordinary" arteriosclerosis with age, it doesn't involve cholesterol and it does involve calcification! Lots more posts there... But the young ones being more susceptible to cholesterol poisoning is also interesting. Perhaps they are using foam cells as a surrogate for the Lp(a) they cannot make.

There are tie-ins for all of these papers with papers on the list to blog about, especially insulin resistance and GAG metabolism...

BTW mid summer hedgehogs are anything but slow, they used to leg it around our garden in Berkshire!

Sigh re serotonin.

Hi Winalot, I suspect that worrying about Lp(a) is bad for you, especially if you are never hyperinsulinaemic or hyperglycaemic!


donny said...

Whoops. Make that a fall hedgehog.

Pasi said...

Thank you very much for this information on Lp(a) and intima media thickening!

One quite interesting thing is that rosiglitazone (Avandia) and other thiazolidenediones will increase Lp(a):

Avandia has been lately in headlines:

Rosiglitazone is a PPARg agonist which restores the function of adipose tissue. I don't think that increase of Lp(a) is straight forward related to PPARg agonism since EPA has opposite effects on Lp(a) and it also acts as a PPARg activator:

How and where Lp(a) is formed? How it's formation is regulated?

Winalot said...

Hi Peter,

True on the uneccessary worrying.

I'm sure if I got a barrage of blood tests and the results were not as good as I expected it would be worse than not having them in the first place!

The other point echoes Kurts recent post, that I'm generally doing everything I can whether I'm healthy or not, so why stress over blood results?

Thanks for all your efforts in relaying this information to someone like myself where the science is beyond me.

I tend to skip to your laymans summaries at the end, so please keep it up!


Winalot said...


One more thing to ask you if I may as you have worldly experience as well as science know-how :-)

I have a bad habit(?) of biting my gums, not grinding my teeth or biting lips, but the skin on the inside of my mouth.

I've done this so long I actually have wrinkles on my cheeks where I contort to chew the skin.

If I make a concerted effort I can sometimes stop long enough for the skin to smoothly reform, but since going zero carb I've noticed this getting worse (more chewing & biting, more often).

I know the habit itself is probably strong but I can't help thinking there's something health-wise amiss?

I used to think it was my in-built calorie counter as it tended to lessen as the day went on and my "tank got full". Almost like I was eating myself :-)

I tested this out by pushing calories up and up but no conclusive results.

My other theory was one I don't see discussed much and that's food volume in the stomach. I noticed that when I ate a lot of mince and all the dripping I didn't chew my gums as much, as I felt pretty full. Have tried eating more lettuce with my meat to bulk it up but so far not sure. I know that eating VLC doesn't fill me up as my high-fibre past.

As you can tell I've thought about this a bit and would like to crack it. Wish it was just a micro-nutrient that was missing!


Taka said...

Nice shot on the TTG, Peter! The key question is what is actually damaging the arterial wall here. I don't think it's the sugar directly in people with normal insulin sensitivity. Also the idea of palmitic acid induced insulin resistance leading to hyperglycaemia doesn't seem right to me because we have probably consumed the carbs with some fat throughout our evolution. The working muscle will soak the glucose even if some saturated fat is floating around because it's the preferred energy source.

One suspect may be protein malnutrition so there is not enough building blocks for maintaining the arterial elasticity. Elastin has similar amino acids composition as collagen so it's better to eat your gelatin rather than lean meat (or supplement the infamous BCAAs). Seems like Peat is right here again -

The key suspect for me is, however, nothing else than our old well known gout. The uric acid crystals are pretty sharp and on their way down to the big toes pulled by the gravity field they are making numerous cuts in the arterial walls. Now what raises the uric acid apart from the fructose? Urate is the end product of disassembling DNA bases so anything promoting apoptosis will elevate it. You may be just digesting too much purine rich food like oysters but it's more likely that the source is your own cells dying inside the body. And those cells could be DNA rich cells such as the germ cells not being properly disposed off by a regular activity ...

donny said...

Maybe we lack uricase because we developed in a high ROS environment?

Birds lack uricase, and are also high-energy producers. Exercise increases oxidation of uric acid to allantoin. Not enough to keep uric acid from being high in the urine, but maybe enough to interfere with crystal formation?

These guys compare allantoin to vitamin c. I don't have access to the article, but just the preview itself is interesting.

"The similarity of energy characteristics of reactions of hydroxylation of allantoin and vitamin C should determine the similarity of their biological effects in model systems in vitro and in vivo. In view of this, we performed comparative evaluation of the ability of allantoin, ascorbic acid, and p-aminobenzoic acid (PABA) to quench free-radical processes and inactivate genotoxicity of hydrogen peroxide."

I wonder if this stuff shortens the lives of glucose-blocked nematode worms? And whether uric acid would have the same effect, or not.

Wikipedia on allantoin;
Manufacturers cite several beneficial effects for allantoin as an active ingredient in over-the-counter cosmetics: a moisturizing and keratolytic effect, increasing the water content of the extracellular matrix and enhancing the desquamation of upper layers of dead skin cells, increasing the smoothness of the skin; promotion of cell proliferation and wound healing

That worm study did mention something about collagen... Calorie restricted mice live longer (the ones that don't die younger, anyways) and heal slower.

donny said...

Uric acid as a precursor for allantoin, allantoin perhaps a tool in the repair kit. Uric acid increases blood pressure.

"Interestingly, raising uric acid levels in rats resulted in increased BP and the development of microvascular disease (resembling arteriolosclerosis) in the kidneys.17-18 The mechanism of hypertension was shown to be caused by a uric acid–mediated reduction in endothelial nitric oxide levels19-20 and stimulation of renin expression.18 Studies in humans have also correlated uric acid levels with both endothelial dysfunction21-22 and elevated plasma renin activity"

"Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism"

"The previous experiments were performed under low-salt-diet conditions, because the effect of hyperuricemia on blood pressure is most pronounced under these dietary conditions"


They used oxonic acid to block uricase here.

They show uric acid as increasing smooth muscle cell proliferation in isolated cells from rats. By adding uric acid. I wonder if any of it oxidized?

They show arteriosclerosis in rat kidneys. They don't show what happens to the elevated uric acid once it reaches the kidney. The kidney would be a major site for uric acid oxidation, which is also allantoin synthesis.
How come the elevated uric acid levels didn't cause arteriosclerosis outside of the kidneys?

Vasoconstriction might be important at some point in the healing process. Would you stretch out a balloon before putting a rubber patch on it?

(Somebody once said that way better. Something about old and new patches and wineskins;)

Peter said...

Hi Taka, I suspect that physical trauma is probably the main source of micro damage as Willis explained out (I'll go back to Willis in future posts). Willis used scurvy in guinea pigs to weaken collagen. You can use copper deficiency to weaken elastin in swine. You can glycate both of them to reduce their ability to yield under pressure. You can increase pressure. You can get squeezed through your mother's pelvis. There is quite a list of ways to affect trauma. Where does response to injury become pathology?

Donny, Urate is fascinating. Who would have thought that the primary antioxidant in our blood would cause so many problems???? Did you know that JK is very pro hyperuricaemia, in the absence of metabolic syndrome? At the moment that rates as religion.