The fascinating adventures of glutamic acid and its metabolites

Okay. Leptin is intimately involved in glutamic acid metabolism. That seems to be established. Lets look at some basic glutamic acid stuff.



http://www.ncbi.nlm.nih.gov/pubmed/18187428

"Acute effect of poly-gamma-glutamic acid on calcium absorption in post-menopausal women"

A number of food constituents have a positive [1–3] or negative [4–6] effect on intestinal Ca absorption in humans. Ca solubility is increased in the small intestine of rats given poly--glutamic acid (PGA), a polymer in which a large number of glutamic acid molecules are combined by -linkages [7]. PGA is a component of natto mucilage obtained from fermented soybeans, a traditional Japanese food; estimates of natto consumption in Japan suggest that the daily intake of PGA is approximately 16 mg/day. PGA can also be produced by fermentation of Bacillus natto in a liquid medium [8] and it has been considered as a candidate compound for functional foods aimed at promoting bone health. A recent report suggests that the consumption of natto is associated with reduced bone loss in postmenopausal Japanese women [9]. We hypothesise that the mode of action of PGA is increased Ca solubility in the gut lumen [7] thereby increasing paracellular Ca absorption in the lower intestine.

Another glutamic acid calcium connection. Obviously just a coincidence, any attempt to follow the significance of glutamic acid/calcium around the body would obviously be naive.

Another coincidence. Vitamin k, which is necessary for the gamma-carboxylation of glutamic acid residues (don't worry, I don't know what that means, either), is necessary for the proper control of calcium throughout the body. For one thing, it prevents the calcification of soft tissues.

Glutamic acid is anaplerotic, which means that it feeds into the Krebs cycle. Mitochondrial respiration. One thing about the Krebs cycle-- you can't burn fat without it. So if a cell needs to burn fat, there's no way to do it without glutamic acid.

There may be a problem in this. Brain cells get excited when they see glutamate, the salt of glutamic acid.

Glutamate transporters are found in neuronal and glial membranes. They rapidly remove glutamate from the extracellular space. In brain injury or disease, they can work in reverse and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death, and is called excitoxicity.

That's wikipedia. Again with the calcium.

http://www.ncbi.nlm.nih.gov/pubmed/19587091

Glutamate is a main constituent of dietary protein and is also consumed in many prepared foods as an additive in the form of monosodium glutamate. Evidence from human and animal studies indicates that glutamate is a major oxidative fuel for the gut and that dietary glutamate is extensively metabolized in first pass by the intestine. Glutamate also is an important precursor for bioactive molecules, including glutathione, and functions as a key neurotransmitter. The dominant role of glutamate as an oxidative fuel may have therapeutic potential for improving function of the infant gut, which exhibits a high rate of epithelial cell turnover. Our recent studies in infant pigs show that when glutamate is fed at higher (4-fold) than normal dietary quantities, most glutamate molecules are either oxidized or metabolized by the mucosa into other nonessential amino acids. Glutamate is not considered to be a dietary essential, but recent studies suggest that the level of glutamate in the diet can affect the oxidation of some essential amino acids, namely leucine. Given that
substantial oxidation of leucine occurs in the gut, ongoing studies are investigating whether dietary glutamate affects the oxidation of leucine in the intestinal epithelial cells. Our studies also suggest that at high dietary intakes, free glutamate may be absorbed by the stomach as well as the small intestine, thus implicating the gastric mucosa in the metabolism of dietary glutamate. Glutamate is a key excitatory amino acid, and metabolism and neural sensing of dietary glutamate in the developing gastric mucosa, which is poorly developed in premature infants, may play a functional role in gastric emptying. These and other recent reports raise the question as to the metabolic role of glutamate in gastric function. The physiologic significance of glutamate as an oxidative fuel and its potential role in gastric function during infancy are discussed.

So. The tissues in the body that get the first look at glutamate dig in deep.

Here's a tidbit;

http://www.ncbi.nlm.nih.gov/pubmed/121936

Rats received 3H-mannitol, which marks the intactness of the blood-brain barrier, and 14C glutamate or 14C-aspartate by intracardiac injection after oral gavage with water, monosodium glutamate, monosodium aspartate, or sodium chloride (doses equiosmolar to 4 g/kg monosodium glutamate). Thirty min later, various brain regions (e.g., cerebellum, cortex, hypothalamus, and striatum) were assayed for tritium and carbon-14. In most regions in most animals given monosodium glutamate or hypertonic saline, the level of the carbon-14 acidic amino acid tended to parallel the extent of damage incurred by the blood-brain barrier, as indicated by high levels of tritium-labelled mannitol. These data suggest that severe hyperosmolarity may be a prerequisite for monosodium glutamate to produce neurotoxic changes, and may explain why elective dietary consumption of enormous quantities of glutamate, by animals given free access to water, fails to induce brain lesions.

No comment, you never know what might come in useful. Edit; MSG is accused of being an asthma trigger. That "hyperosmolarity" thing may be related to that, there's a lot of stuff out there about asthma and sodium.

L-glutamic acid is oxidized by the brain to alphaketoglutaric acid, NH3 and later CO2 and H2O and is the only amino acid that on its own can maintain brain slice
respiration (Weil-Malherbe, 1936)

Mouse. Mice aged 2 to 9 days were killed 1 to 48 hours after single subcutaneous injection of monosodium glutamate at doses from 0.5-4 µg/kg, lesions seen in the preoptic and arcuate nuclei of the hypothalamic region on the roof and floor of the third ventricle and in scattered neurons in the nuclei tuberales. No pituitary lesions were seen but sub-commissural and subfornical organs exhibited intracellular oedema and neuronal necrosis. Adult mice given subcutaneously 5-7 µg/kg monosodium L-glutamate showed similar lesions. Similar lesions were seen in another strain of mouse and in neonatal rats
(Olney, 1969b).

After a single subcutaneous injection of monosodium glutamate at 4 g/kg into neonatal mice aged 9-10 days. the animals were killed from 30 minutes to48 hours. The retinas showed an acute lesion on electron microscopy with swelling dendrites and early neuronal changes leading to necrosis followed by phagocytosis (Olney, 1969a). Sixty-five neonatal mice aged 10-12 days received single oral very high loads of monosodium glutamate at 0.5, 0.75, 1.0 and 2.0 g/kg
body-weight by gavage. 10 were controls and 54 mice received other amounts. After 3-6 hours all treated animals were killed by perfusion. Brain damage as evidenced by necrotic neurons was evident in arcuate nuclei of 51 animals. 62 per cent. at
0.5 g/kg, 81 per cent. at 0.75 g/kg, 100 per cent. at 1 g/kg and 100 per cent. at 2 g/kg. The lesions were identical both by light and electron microscopy to s.c. produced lesions. The number of necrotic neurons rose approximately with dose.

http://www.inchem.org/documents/jecfa/jecmono/v48aje09.htm


That's from a WHO toxin report on MSG. So what's wrong with MSG?

There may be a few problems. Glutamate may travel around the body more freely. Rats that drank MSG water or plain water at will in one study ate more food, but were leaner. L Glutamine causes fat cells to become insulin resistant. Glutamate and L Glutamine are both obvious precursors to Glutamic acid, which makes them precursors to several points of entry into the Krebs Cycle.

So what happens in the brain on MSG, if free access to water isn't given? Well, what if MSG has the same effect on calcium as glutamate? But suppose that the brain also can't properly metabolize MSG, perhaps into Krebs cycle metabolites, because of the sodium. Sodium and Glutamic acid have their own taste receptors, as well as regulatory hormones (aldosterone and leptin). Cells may have difficulty regulating these two substances if they are bound together. The sodium further complicates things through its effect on osmolarity. This much seems clear. Disregulation of sodium and glutamate (which means disregulation of calcium) cannot be a good idea.

Should we be looking for hormones that regulate sour and bitter substances?

That bit I highlighted in red. Glutamic acid seems to be the preferred fuel for human cells. All of them. We can't live off a diet of pure glutamic acid, of course. Much of glucose and fat metabolism is to the purpose of rationing our use of glutamic acid.

Eat glucose. Your pancreas puts out insulin, just like a yeast cell does, the purpose of the insulin as far as the pancreas is concerned is to bring it some glucose. But the pancreas isn't very good at this, and is horribly insulin resistant, so it ends up putting out enough insulin to regulate blood glucose throughout the body. Some of the glucose and insulin travels to the muscle; this has the effect of spurring glutamine production in the muscle. The thing about glutamine; it's one more step away from the various metabolites of the Krebs cycle that glutamic acid is a precursor to. So this may be a sort of safety valve, lowering free glutamic acid levels in the cell, glutamine is more inert. Being similar to glutamic acid, glutamine might interfere with enzymic actions that produce those metabolites of the Krebs cycle, as well.

Glutamine crosses the blood-brain barrier by a mediated process.

Here's something;

This study examines the effects of middle cerebral artery (MCA) occlusion in the rat on blood to brain glutamine transport, a potential marker of early endothelial cell dysfunction. It also examines whether the effects of ischemia on glutamine transport are exacerbated by hyperglycemia. In pentobarbital-anesthetized rats, 4 hours of MCA occlusion resulted in a marked decline in the influx rate constant for [14C]L-glutamine from 16.1+/-1.2 microL.g(-1).min(-1) in the contralateral hemisphere to 7.3+/-2.5 microL.g(-1).min(-1) in the ischemic core (P <>



http://www.biomedexperts.com/Abstract.bme/9886358/Blood-brain_barrier_glutamine_transport_during_normoglycemic_and_hyperglycemic_focal_cerebral_ischemia

Mess with sodium, and you mess with glutamine, which means you mess with glutamic acid. Which messes you up. They only theorize that sodium is the cause of the cell swelling. Potassium uptake is regulated directly by insulin. So obviously glucose itself must have some effect on osmalarity, necessitating that extra potassium. And in all this mess, how is the brain to be properly fed? And how is it to maintain the integrity of its tissues, if it isn't properly fed. And

L-glutamic acid ...is the only amino acid that on its own can maintain
brain slice respiration.

This is why we have leptin, which is the "insulin" for glutamic acid. It's kind of important.

Another possible place L glutamine produced by muscle might wander over to is adipose tissue. L Glutamine causes fat cells to become insulin resistant. Why are muscles insulin-resistant? Fat feeds into the Krebs cycle, lowering the need for glucose. Why are fat cells insulin-resistant? Fat feeds into the Krebs cycle, lowering the need for glucose. Somehow mediated by glutamine. Less need for glucose translates into a decrease in cell levels of glucose, and if cell levels of glucose are a rate-limiting factor for triglyceride synthesis (um, duh) then free fatty acids in the cell tend to stay... free. Which means they can be oxidized.

Insulin suppresses and counterregulatory hormones increase proteolysis. Therefore, if proteolysis were a major factor determining amino acid fluxes in plasma, one would expect release of glutamine into plasma to be suppressed by insulin under euglycemic conditions and to be stimulated under hypoglycemic conditions. However, release of glutamine into plasma remains unaltered or increases during euglycemic hyperinsulinemia and decreases during insulin-induced hypoglycemia. To investigate the mechanisms for these paradoxical observations and the role of skeletal muscle, we infused overnight fasted volunteers with [U-14C] glutamine and measured release of glutamine into plasma, its removal from plasma, and forearm glutamine net balance, fractional extraction, uptake and release during 4-hour euglycemic (--5.0 mmol/L, n = 7) and hypoglycemic (∼3.1 mmol/L, n = 8) hyperinsulinemic (∼230 pmol/L) clamp experiments. During the euglycemic clamps, plasma glutamine uptake and release (both P <.05) and forearm muscle glutamine fractional extraction(P <.05), uptake (P < .02) and release (P <.01) all increased, whereas forearm glutamine net balance remained unchanged. The increase in muscle glutamine release (from 1.85 ± 0.26 to 2.18 ± 0.30 μmol . kg-1 . min-1) accounted for approximately 60% of the increase in total glutamine release into plasma (from 5.54 ± 0.47 to 6.10 ± 0.64 μmol . kg-1 . min-1) and correlated positively with the increase in muscle glucose uptake (r = 0.80, P <.03). During the hypoglycemic clamps, plasma glutamine uptake and release and forearm glutamine release remained unaltered, but forearm glutamine fractional extraction and uptake decreased approximately 25% (both P <.01) so that forearm glutamine net release increased from 0.37 ± 0.06 to 0.61 ± 0.09 μmol . kg-1. min-1 (P <.03). We conclude that skeletal muscle is largely responsible for the increased release of glutamine into plasma during euglycemic hyperinsulinemia in humans, and that this may be due to increased conversion of glucose to glutamine as part of the glucose-glutamine cycle; during hypoglycemic hyperinsulinemia decreased glutamine uptake by skeletal muscle may be important for providing substrate for increased glutamine gluconeogenesis.

I see cells dumping glutamine when insulin forces them to switch over to glucose metabolism. What do you see?

http://cat.inist.fr/?aModele=afficheN&cpsidt=16115950

Aims/hypothesis Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a high-fat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal.

Materials and methods

Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/ immunoblotting were performed. Results HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulin-induced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFα and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IκB kinase subunit β (IKKβ) and mammalian target of rapamycin (mTOR) activity in the liver, muscle
and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats.
Conclusions/interpretation Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKβ, while improving insulin signalling in liver and muscle.

http://cat.inist.fr/?aModele=afficheN&cpsidt=18994160

Glutamine increases muscle insulin sensitivity by inducing fat insulin resistance? I think tumour necrosis factor alpha and Il-6 levels in this case are probably signs that the animals are better maintained.

Reduced RQ and an increase in oxygen use-- that usually means more fat used for energy. The rats fat (and bone) probably puts out less leptin, making the muscles less biased towards fat oxidation and more open to the possibilities of glucose. Less leptin plus less insulin in the muscle cells might mean less metabolic over-steering.

An interesting note. The insulin in the first study made muscles put out glutamine. Do they put out enough glutamine to cause insulin resistance in the fat cells, which would make the muscle cells more insulin sensitive? Is this a significant part of the regulation of body fat?

WAIT A MINUTE. It sort of sounds like the muscles are trying to reduce the glucose in the system, like this is a vote for glutamine and or fat metabolism. Insulin sensitivity in muscles means making glutamine, rather than burning glucose?

This reminds me of those "Can you imagine a world without sand" type movies back in, well, not back in my school days. But you know, back in the school days they show in sitcoms. Glutamate, glutamine. The most dirt-common proteins in the body. So of course they're crucial, I guess.

Is metabolic syndrome a blood glutamine deficiency? At least, a functional one? I did pose it as a question this time, so if it's off to the funny farm, at least this post probably won't be the cause.

Tumour necrosis factor to the rescue. No, really.

Abstract We examined the effects of lacking tumor necrosis factor α (TNFα) on the healing process of a cutaneous wound in mice using TNFα-deficient mice. A full-thickness circular cutaneous wound 5.0 mm in diameter was produced in the dorsal skin of wild-type (WT) or TNFα-null (KO) mice. After specific intervals of healing, the healing pattern was evaluated by macroscopic observation, histology, immunohistochemistry, or real-time reverse transcription-polymerase chain reaction. Effect of Smad7 gene transfer on the healing phenotype of KO mice was also examined. The results showed that loss of TNFα promotes granulation tissue formation and retards reepithelialization in a circular wound in mouse dorsal skin. Immunohistochemistry showed that distribution of macrophages and myofibroblasts in newly generated granulation tissue seemed similar between WT and KO mice. However, lacking TNFα enhanced mRNA expression of TGFβ1 and collagen Iα2 in such tissue. Smad7 gene transfer counteracted excess granulation tissue formation in KO mice. In conclusion, lacking TNFα potentiates Smad-mediated fibrogenic reaction in healing dermis and retards
reepithelialization in a healing mouse cutaneous wound."

http://www.fasebj.org/cgi/reprint/03-0068fjev1.pdf

From wikipedia;

Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals.

Tumour necrosis factor alpha "inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase."

Whatever that means. But anyways, it reduces the action of insulin in the cell. Which is, insulin resistance. Bad, right? But if it doesn't do that, what happens to wound healing?

If you block glucose metabolism in nematode worms, they live twice as long. And collagen one production is decreased. Glucose metabolism is clearly important to collagen formation. And healing. Probably in arteries as well as skin.

And the disregulation of energy source, the wrong blend of glucose and fat metabolism, should lead to what? Poorly-healed wounds. Including in arteries. Too little collagen (not enough glucose) will make for patches lacking strength. Too much collagen will make for well, in the extreme, wounds that don't even close properly?

Okay. So tumour necrosis factor alpha induces insulin resistance in an arterial lesion. Which should down-regulate insulin signalling. Which should stimulate the oxidation of fat, which will facilitate the healing process. So LDL to the rescue! LDL cholesterol shows up with lots of tasty fat, mitochondria start to party! So some serious healing should take place. What goes wrong?

Why do you end up with an atherosclerotic plaque, poorly healed, with a core of lipid-rich pudding?

Well, why do muscle cells fill up with fat in lipid storage myopies? One form of lipid storage myopy occurs when muscle cell leptin receptors are deficient in activity or presence. Leptin facilitates the use of fat for energy. Fat cells are less sensitive to their own leptin than other cells; but they do have leptin receptors.

Atherosclerotic plaque, the human kind with the lipid core, looks an awful lot like a wound with a lipid storage disease. To the untrained eye, anyways, and that's the only kind I've got. Lipid storage disease is really just a relative inability to metabolize lipids for energy. Something keeps the whatever-you-call-em, the immune and repair cells from properly metabolizing fat.

What does this? How about signing up for a study of the effect of massive doses of certain antioxidants on the development of heart disease? Messing around with your antioxidant status can seriously mess up your ability to metabolize fat. The mainstream calls this anti-inflammatory; less free radicals, less oxidized cholesterol, less heart disease. Well, that just plain didn't work out.

One thing about omega 6 fatty acids; they contain a whole crapload of vitamin e. The vitamin e is there to protect the fatty acids from oxidation; including the type encouraged by mitochondria.

Of course, this predicts that interventions that facilitate the use of fat for energy will help arteries heal, at least when the thing going wrong is arterial lipid storage disease.


http://www.sciencedirect.com/science



"ApoE Promotes the Proteolytic Degradation of Amyloid Plaque"

That isn't quite the name of that study, there was a greek letter in there that pasted wrong. There's a product called Amylin; Dr Bernstein uses it for some of his patients to reduce cravings for sugar, and there are some studies showing it increasing leptin sensitivity. Amylin is a drug based on the hormone amyloid. Amyloid is produced in the pancreas, along with insulin. It's also produced in the brain.


http://people.csail.mit.edu/seneff/alzheimers_statins.html

APOE-4: The Clue to Why Low Fat Diet and Statins may Cause
Alzheimer's
by Stephanie Seneff

Amyloid-beta (also known as "abeta") is the substance that forms the famous plaque that accumulates in the brains of Alzheimer's patients. It has been believed by many (but not all) in the research community that amyloid-beta is the principal cause of Alzheimer's, and as a consequence, researchers are actively seeking drugs that might destroy it. However, amyloid beta has the unique capability of stimulating the production of an enzyme, lactate dehydrogenase, which promotes the breakdown of pyruvate (the product of anaerobic glucose metabolism) into lactate, through an anaerobic fermentation process, with the further production of a substantial amount of ATP.

People with APOE4 genotype get more heart disease, more alzheimer's. Amyloid-beta accumulates in the brains of Alzheimer's patients. Amyloid-beta promotes the proper metabolism of carbohydrates, that's a good thing. But there's a time when you don't want to promote the metabolism of glucose, lactate, etc.-- that is, when high-gear mitochondrial respiration, the preference of fat for energy, and the spewing out of free radicals is desirable. Like um, when you're trying to clear up a serious case of arterial lipid storage disease, for instance.

Let's look at some mice.

http://atvb.ahajournals.org/cgi/content/abstract/20/12/2587

Abstract—Most previous studies of atherosclerosis in hyperlipidemic mouse models have focused their investigations on lesions within the aorta or aortic sinus in young animals. None of these studies has demonstrated clinically significant advanced lesions. We previously mapped the distribution of lesions throughout the arterial tree of apolipoprotein E knockout (apoE-/-) mice between the ages of 24 and 60 weeks. We found that the innominate artery, a small vessel connecting the aortic arch to the right subclavian and right carotid artery, exhibits a highly consistent rate of lesion progression and develops a narrowed vessel characterized by atrophic media and perivascular inflammation. The present study reports the characteristics of advanced lesions in the innominate artery of apoE-/- mice aged 42 to 60 weeks. In animals aged 42 to 54 weeks, there is a very high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap. By 60 weeks of age, the lesions are characterized by the presence of collagen-rich fibrofatty nodules often flanked by lateral xanthomas. The processes underlying these changes in the innominate artery of older apoE-/- mice could well be a model for the critical processes leading to the breakdown and healing of the human atherosclerotic plaque.

So what have we here? Knock out apoE. If I'm looking at this right, this improves glucose metabolism, the feeding of lactic acid into the Krebs cycle. No need for fat here, we're really good at burning glucose! Life is good!

Except that it isn't. "Collagen-rich fibrofatty nodules"-- um, encouraging glucose metabolism seems to have caused excess collagen growth.

Also

In animals aged 42 to 54 weeks, there is a very high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap

This is really freaking bad. Really really really bad. Loss of the fibrous cap? What could have caused that? And does this remind anybody of the study at the top of this page, the one that says

The results showed that loss of TNFa promotes granulation tissue formation
and retards reepitheialization in a circular wound in mouse dorsal skin

Doesn't the effect of an ApoE type that just happens to be associated with increased levels of a hormone that facilitates glucose metabolism on healing in mouse arteries sort of kind of resemble the effect of the lack of a hormone that discourages glucose metabolism on healing in mouse skin? Oh my, what a startling coincidence!

Our uric acid is trying to keep us alive

Or maybe I'm holding this thing upside down.

http://high-fat-nutrition.blogspot.com/search/label/Worms%20and%20Stress%3A%20Live%20long%20and%20Prosper

Peter says it better than I will, but I'll give a quick run through. You block glucose metabolism in some worms, and it doubles their lifespan. When the worm's mitochondria switch to burning fat, they start spewing out all kinds of free radicals. Lots of fat being burned, the energy is used for repair, to attack invading bacteria, to fight cancer, lots of good stuff. Antioxidants are crucial enzymes, not just generic antioxidants.
Feed the worms some antioxidants, vitamin c, vitamin e, or n-acetyl cysteine, and the increase in the worms lifespan disappears, along with the dangerous free radicals. It's not about wear and tear, wear and repair is the rule.

So what's been established? The mitochondrial fires can be severely decreased by changing the antioxidants present.

Uric acid is itself an antioxidant, as is allantoin. So introducing either one of these into the environment of a cell will change the antioxidant status of the cell, which could have consequences to energy production. Energy availability is enormously important to cell proliferation.

Human beings have a thing called physiological insulin resistance, where cells are resistant to insulin and glucose. This has the obvious benefit of sparing glucose for tissues that need glucose even when glucose is short, such as the brain. It has another benefit; if the body hopes to benefit in some way by the production of free radicals, insulin resistance is just the thing. Insulin resistant cells will switch over to burning fat. (If the body is busy fighting something or producing energy to heal a wound, dousing the fire with a little vitamin e, vitamin c, or n acetyl cysteine at this point might not be wise.)

http://jama.ama-assn.org/cgi/reprint/266/21/3008

Based on the data presented herein, it seems reasonable to conclude that differences in the ability of insulin to stimulate glucose uptake play a role in the regulation of serum uric acid concentration within a normal, healthy population, and this action is mediated by changes in the renal handling of uric acid. Furthermore, the relationships defined in the study (summarized in Fig 4) provide the experimental basis for this conclusion. We suggest that resistance to insulin-mediated glucose uptake and/or the compensatory hyperinsulinemia associated with this defect decrease urinary uric acid clearance, with a subsequent increase in serum uric acid concentration. More specific, we propose that the greater the degree of insulin resistance, the lower the uric acid clearance. Based on the data presented herein, it seems reasonable to conclude that differences in the ability of insulin to stimulate glucose uptake play a role in the regulation of serum uric acid concentration within a normal, healthy population, and this action is mediated by changes in the renal handling of uric acid. Furthermore, the relationships defined in the study (summarized in Fig 4) provide the experimental basis for this conclusion. We suggest that resistance to insulin-mediated glucose uptake and/or the compensatory hyperinsulinemia associated with this defect decrease urinary uric acid clearance, with a subsequent increase in serum uric acid concentration. More specific, we propose that the greater the degree of insulin resistance, the lower the uric acid clearance and the higher the serum uric acid concentration

Dr Richard Bernstein has been teaching diabetic patients how to achieve normal blood sugar levels using a very low carbohydrate diet and minimal insulin injections. In his book Dr Bernstein's Diabetic Solution, Dr Bernstein reveals that it is virtually impossible to achieve good blood sugars if an infection is present. Infection is a major insulin-resistance culprit. Time for repair. Time for the free radicals to come out to play? Mitochondrial fat-munchers to the rescue, again.

And, in insulin resistance, serum uric acid goes up? Part of the healing process?

Fructose has been proposed as the cause of gout and excess uric acid, through depletion of ATP in the liver (the adenosine part of adenosine tri phosphate is a purine.) But fructose is also seriously implicated in the invasion of the body by lipopolysaccharides (biofilm, a matrix of complex sugars and yeasties and microbes and stuff.) Lipopolysaccharides release endotoxins into the body that can cause cancer, fatty liver, etc.

Fructose gives mice and rats fatty liver, high blood pressure, etc. This can be lessened by glycine and taurine, both of which protect the body against endotoxins, (although I'm not sure endotoxins are the villain here) and are actually involved in their removal from the body through bile. Glycine used to be used to treat gout, back before they discovered allopurinol, which disrupts purine metabolism so that less uric acid is produced.

Glycine increased the output of uric acid in the urine. That's why they used it. But glycine is also a purine--and very cheap-- so of course it fell out of favour. They worried that the uric acid in the urine was formed from the breakdown of the glycine. I sort of doubt it.

So something that basically helps the body to fight infection has been seen reversing "metabolic syndrome" in rodents. Remove the infection, remove the insulin resistance? Remove the infection, reverse the uric acid elevation? Because both of these are just part of the body's defence and repair system?

http://www.cababstractsplus.org/abstracts/Abstract.aspx?AcNo=20053171423

Accumulation of collagen and changes in its physiochemical properties contribute to the development of secondary complications of diabetes. We undertook this study to determine the effects of taurine on the content and characteristics of collagen isolated from the tail tendon of rats fed with high fructose diet. The rats were divided into four groups of six each: control group (CON), taurine-supplemented control group (CON+TAU), taurine supplemented (FRU+TAU) group, and non-supplemented fructose-fed group (FRU). The physicochemical properties of collagen were studied. Fructose administration caused the accumulation of collagen in tail tendon. Enhanced glycation and advanced glycation end products (AGE)-linked fluorescence together with alterations in aldehyde content, solubility pattern, susceptibility to
denaturing agents and shrinkage temperature were observed in fructose-fed rats. An elevated β component of type I collagen was observed from the SDS gel pattern of collagen from the fructose-fed rats. Simultaneous administration of taurine alleviated these changes. Taurine administration to fructose-fed rats had a positive influence on both quantitative and qualitative properties of collagen. Results indicate the role of taurine in delaying diabetic complications. It can be used as an adjuvant therapeutic measure in the management of diabetes and its complications.

Thickened tails as a reaction to infection? Does it have to be a real infection?

Inactivation of Kupffer cells prevents alcohol-induced liver injury, and hypoxia subsequent to a hypermetabolic state caused by activated Kupffer cells probably is involved in the mechanism. Glycine is known to prevent hepatic reperfusion
injury. The purpose of this study was to determine whether glycine prevents
alcohol-induced liver injury in vivo.

METHODS: Male Wistar rats were exposed to ethanol (10-12 g.kg-1.day-1) continuously for up to 4 weeks via an intragastric feeding protocol. The effect of glycine on the first-pass metabolism of ethanol was also examined in vivo, and the effect on alcohol metabolism was estimated specifically in perfused liver.

RESULTS: Glycine decreased ethanol concentrations precipitously in urine, breath, peripheral blood, portal blood, feces, and stomach contents. Serum aspartate amino-transferase levels were elevated to 183 U/L after 4 weeks of ethanol-treatment. In contrast, values were significantly lower in rats given glycine along with ethanol. Hepatic steatosis and necrosis also were reduced significantly by glycine. Glycine dramatically increased the first-pass elimination of ethanol in vivo but had no effect on alcohol metabolism in the perfused liver.

CONCLUSIONS: Glycine minimizes alcohol-induced liver injury in vivo by preventing ethanol from reaching the liver by activating first-pass metabolism in the stomach.

http://www.ncbi.nlm.nih.gov/pubmed/8613061



Just the abstract again. Kupffer cells are macrophages, part of the immune system. So if glycine reduced activation of Kupffer cells, reversing the implied infection? In a human, would this reversal of infection also permit removal of more uric acid in the urine?

http://ajpcell.physiology.org/cgi/reprint/293/2/C584


I love this one.

Our results support previous epidemiological studies and animal models
of hyperuricemia, which suggests an involvement of uric acid in the pathogenesis of the metabolic syndrome,and provide a possible molecular mechanism for this role based on the finding that soluble uric acid affects adipocytes directly by inducing NADPH oxidase-dependent oxidative stress.
We suggest that hyperuricemia can be one of the causal factors inducing oxidative stress followed by a proinflammatory process and endocrine dysfunction in the adipose tissue, thereby contributing to the pathogenesis of the metabolic
syndrome and cardiovascular disease.

So, whatta we got here? Uric acid causes fat cells to start spewing out free radicals. Uric acid facilitates the oxidation of fat. Uric acid is associated with inflammation. Inflammation is a cause of insulin resistance, which is the preference for fatty acid oxidation over glucose.

Inflammation is the body trying to heal or fight off invaders. Uric acid is part of that process.

Human beings and birds are both long-lived. Human beings and birds both lack uricase, which breaks down uric acid. Uric acid is an antioxidant/pro-oxidant, affecting oxidation status. Uric acid can promote high-gear mitochondria fat-munching. Causing an increase in free radicals.

http://www.drproctor.com/rev/ascorbicuric.htm

Similar Functions of Uric Acid and Ascorbate in Man

Pointing out the structural similarity between uric acid and the stimulant purines caffeine and theophylline, Orowan (1) first proposed that the emergence of intelligence in the primate line might arise from a single evolutionary event, the loss of the enzyme uricase, with the result that uric acid became the end product of purine metabolism. The only non-primate mammalian strain whose final purine metabolite is uric acid is the Dalmatian dog.
Haldane (2), taking issue with this suggestion, proposed two hypotheses: thatindividuals with high serum uric acid levels should show increased intellectual abilities , and that such individuals should be unusually resistant to certain types of fatigue. Neither one of these has received much experimental support, although serum uric acid levels have been correlated with social class, achievement, and achievement -oriented behavior. ( for a review of such work, see Muller et al (3)).
I would like to propose that the loss of uricase in the primate line may be connected with another biochemical lesion which is unique to the primates, namely, the loss of
the ability to synthesise ascorbic acid de novo, As in the case of loss of uricase, this lesion is found in only one non-primate mammalian species ( the guinea pig (4) ). ( Post-publication addendum: also the flying fox.)
The reasoning behind this suggestion is this: a number of the physiological functions of ascorbate are generally considered to be related to the unique electron-donor properties of this compound. Uric acid (along with the rest of the purines ) is also a strong electron-donor (5). In fact, on the somewhat tenuous basis of molecularorbital indices, uric acid may be a better electron-donor than is ascorbate.(6). It therefore seems possible that ( in primates at least ) uric acid has taken over some of the functions of ascorbate.
This suggestion is not to deny any other physiological or psychological function for uric acid, but is advanced to suggest an evolutionary mechanism for the loss of the ability to synthesize ascorbate de novo ( the latter lesion might not be very important in a fruit-eating animal except in times of famine or in the event of a change in diet. ). Any further selective advantage of higher systemic levels of uric acid would tend to establish the double lesion in the population.

Hmm.

This was before the glucose-blocking worm study, of course. The secret to our longevity is little focused bursts of mitochondrial respiration, mediated by uric acid. That's how it looks to me, anyways.

I wasn't kidding. Your antioxidants are trying to kill you.

So you've got this creature. It's a weird thing. It doesn't make vitamin c. It lacks uricase, so instead of peeing allantoin, the oxidized form of uric acid, it pees uric acid itself. This leaves the creature susceptible to a number of things. The vitamin c, scurvy. The high levels of uric acid can make gout a problem, if the diet isn't right.
One thing a creature with low levels of vitamin c needs, besides vitamin c; a system to preserve vitamin c. Linus Pauling observed that sick or wounded animals have elevated levels of vitamin c. Scar tissue has high levels of collagen; vitamin c is needed for the maintenance of collagen. One of the lovely consequences of scurvy is old wounds opening up; broken bones that have long healed will even separate. The tough collagen, an adaptation that should improve the strength of the repair, has become a weakness. So, Pauling's theory was that Lp(a), a lipoprotein that is increased in people in heart disease (and also, according to Peter, in very young infants) is a surrogate for vitamin-c collagen formation. So heart disease is a form of low-grade, prolonged scurvy caused by excessive dependence on the Lp(a) patch to repair arteries. So eating lots of vitamin C (and other nutrients, like lysine, of which collagen is composed) should prevent and reverse heart disease.

How to preserve vitamin c? Well, there's these glut-doohickeys which I understand are somehow involved in the uptake of both glucose and vitamin c, and our doohickeys seem to be set up to keep vitamin c in the system. I direct you to the world wide web if you want to know more about those.

Here's another way; healing demands collagen formation, which demands vitamin c. Even uses it up. When vitamin c is in short supply, it's awfully valuable, you don't want to waste it. Maybe you use up your vitamin c healing a major wound, you wind up with scurvy. Trying to heal is killing you. So you need a way to ration your resources so that the tissues under the most repeat stress (artery branches, etc.) get the collagen they need to toughen up, while avoiding scurvy in the whole body.

Enter uric acid, allantoin, lp(a) and maybe Neu5Gc.



Here's how I see it; "

Edit; how I see it is largely my understanding of what Peter (Hyperlipid) has been explaining it on his blog. The uric acid thing is my fixation.

An artery is wounded. Lipoproteins (ldl "bad" cholesterol) is drawn to the injury site. Ldl cholesterol is a lipoprotein that delivers fat and cholesterol to places where it's needed.

Artery endothelial cells (the cells that make up the inner lining of arteries) have receptors for ldl.
Endothelial cells have mitochondria, which help the cells produce energy from fatty acids or glucose. When mitochondria are happily chomping away on fats, they start spewing out reactive oxygen species, free radicals. The thing about reactive oxygen species is, they tend to oxidize things. Like, for instance, uric acid. Which produces allantoin. Which is, um, permissive of endothelial cell proliferation. Which is, um, pretty obviously a healing process.

What kind of fat do you want fed into your endothelial mitochondria when it's time for some healing?

Well, here's an interesting bit about fish oil vs corn oil;

An increase in reactive oxygen species by dietary fish oil coupled with the attenuation of antioxidant defenses by dietary pectin enhances rat colonocyte apoptosis
Auteur(s) / Author(s)SANDERS Lisa M. (1) ;
HENDERSON Cara E. (1) ; MEE YOUNG HONG (1) ; BARHOUMI Rola (2) ;
BURGHARDT Robert C. (2) ; NAISYIN WANG (3) ; SPINKA Christine M. (3) ;
CARROLL Raymond J. (1 3) ; TURNER Nancy D. (1) ; CHAPKIN Robert
S. (1) ; LUPTON Joanne R. (1) ;
Affiliation(s) du ou des auteurs /
Author(s) Affiliation(s)(1) Faculty of Nutrition, Texas A&M University,
College Station, TX 77843, ETATS-UNIS(2) Department of Veterinary Anatomy and
Public Health, Texas A&M University, College Station, TX 77843,
ETATS-UNIS(3) Department of Statistics, Texas A&M University, College
Station, TX 77843, ETATS-UNIS
Résumé / AbstractWe showed previously that the dietary combination of fish oil, rich in (n-3) fatty acids, and the fermentable fiber pectin enhances colonocyte apoptosis in a rat model of experimentally induced colon cancer. In this study, we propose that the mechanism by which this dietary combination heightens apoptosis is via modulation of the colonocyte redox environment. Male Sprague-Dawley rats (n = 60) were fed 1 of 2 fats (corn oil or fish oil) and 1 of 2 fibers (cellulose or pectin) for 2 wk before determination of reactive oxygen species (ROS), oxidative DNA damage, antioxidant enzyme activity [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)] and apoptosis in isolated colonocytes.

Fish oil enhanced ROS,

whereas the combination of fish oil and pectin suppressed SOD and CAT and enhanced the SOD/CAT ratio compared with a corn oil and cellulose diet. Despite this modulation to a seemingly prooxidant environment, oxidative DNA damage was inversely related to ROS in the fish oil and pectin diet, and apoptosis was enhanced relative to other diets. Furthermore, apoptosis increased exponentially as ROS increased. These results suggest that the enhancement of apoptosis associated with fish oil and pectin feeding may be due to a modulation of the redox environment that promotes ROS-mediated apoptosis.

Do not eat corn oil; beware plant fats high in omega-6 fatty acids in general. Fish oil seems like a very good idea, if you're depending on your blood lipids to ensure that your arteries are healed properly.

Pectin works as an anti-anti-oxidant (pro-oxidant) in the colon? Pretty freakin' cool. Those studies with anti-oxidants, the disappointing ones where vitamin c led to carotid artery thickening, where beta-carotene supplemented smokers got more cancer. Here's what Health Canada has to say about the dangers of vitamin e supplementation;

Recently published studies have suggested that vitamin E supplements not only fail to prevent heart disease and cancer, but may actually harm people who take high doses over a long term. However, these studies are limited by the fact that they involved: people 55 years or older who already had heart disease or diabetes; people with cancer or who previously had cancer; and people who may be at higher risk of developing these diseases.
One study found that patients with heart disease or diabetes who took 400 IU of vitamin E daily for an average of seven years were at a significantly increased risk of
heart failure compared to patients who were not taking vitamin E supplements. This study concluded that high-dose vitamin E supplements (400 IU or greater) should not be taken by patients with heart disease or diabetes.
In another study, daily doses of 400 IU of vitamin E were given to patients receiving
radiation therapy for cancers of the head and neck. The theory was that the antioxidant treatment might reduce the incidence of additional cancers of the same type among these patients. However, it was found that those who received vitamin E supplements were significantly more likely to develop other similar cancers during the supplementation period than those receiving a placebo.

ApoE is a lipoprotein tingy that carries certain fat soluble nutrients around in the blood stream. Antioxidants all. These have a place in the healing and maintenance of the body. But there's a time to oxidize, and then there's a time to anti-oxidize. The ApoE-4 genotype is more prone to heart disease, alzheimers, various cancers, etc. Misdelivery of these vital antioxidants could pretty obviously be dangerous, in light of the importance of reactive oxygen species to the healing and to the cancer-fighting processes.

Vitamin k is an antioxidant. Human atherosclerotic plaque is generally calcified, at least in Western populations. Vitamin k is important to calcium homeostasis-- including the removal of calcium from soft tissues, artery walls, etc. Maybe a bit of a catch-22 there.

You Anti-Oxidants are trying to Kill You

Maybe we lack uricase because we developed in a high ROS environment?http://www.springerlink.com/content/47q5376hv0507243/

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?
http://resources.metapress.com/pdf-preview.axd?code=g6x348hx14737518&size=largest

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.


Uric acid as a precursor for allantoin, allantoin perhaps a tool in the repair kit. Uric acid increases blood pressure.
http://jama.ama-assn.org/cgi/content/full/300/8/924

"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"

http://ajprenal.physiology.org/cgi/content/full/282/6/F991?ijkey=e1d892d3fa02232b64fca5fcd893d456749cfa4e

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

Huh. In this study, they show uric acid as increasing smooth muscle cell proliferation in isolated cells from rats. Uric acid levels were increased by adding uric acid in this part of the study. I wonder if any of it oxidized? (Rhetorical question. Of course it did.

Then they show arteriosclerosis in rat kidneys. The rat's uric acid levels are increased by blocking the oxidation of uric acid. 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?

Maybe an unresolved healing process could lead to an elevation of uric acid, and high blood pressure?

Taking lots of anti-oxidants to prevent oxidative stress might not be a good idea if you depend on reactive oxygen species formation to oxidize uric acid into allantoin to somehow facilitate smooth muscle proliferation and arterial healing.

Most of this post came from some comments I made at Peter's blog (Hyperlipid.) It's what led me to make yesterdays post, and it sort of leads in to the next post, so I thought I'd work it in here.

Your Sialic Acid is Trying to Kill You

Sialic acid content of human low density lipoproteins affects their
interaction with cell receptors and intracellular lipid accumulation.

Low density lipoproteins (LDL) isolated from the plasma of patients with angiographically demonstrable coronary heart disease (CHD) induced accumulation of triglycerides, free cholesterol, and cholesteryl esters in cultured macrophages, smooth muscle cells, and endothelial cells derived from uninvolved intima of human aorta, but not in skin fibroblasts or hepatoma cells. The sialic acid content of LDL from CHD patients was 40-75% lower than that from healthy donors. There was a negative correlation between LDL sialic acid content and the LDL-induced accumulation of total intracellular cholesterol. Neuraminidase treatment of LDL from normal healthy donors produced sialic acid-depleted LDL (Ds-LDL) which was able to stimulate intracellular lipid accumulation. Neuraminidase treatment of LDL from CHD patients further increased its capacity to induce intracellular lipid accumulation. Sialic acid-poor LDL isolated by affinity chromatography of LDL from CHD patients induced a 2- to 4-fold increase of free and esterified cholesterol in human intimal smooth muscle cells. Binding, uptake, and degradation of 125I-labeled Ds-LDL by macrophages and endothelial cells were 1.5- to 2-fold higher than for native LDL. Binding and uptake of Ds-LDL was inhibited 64-93% by the addition of 20-fold excess acetylated LDL (Ac-LDL); in the inverse experiment, the level of inhibition was 35-54%. These data indicate that a sialic acid-poor form of LDL isolated from CHD patients can interact with both native and scavenger LDL receptors. A sialic acid-poor form of LDL may be a naturally occurring ligand that interacts with the scavenger receptor(s) on macrophages and endothelial cells.

http://www.ncbi.nlm.nih.gov/pubmed/1512508?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_SingleItemSupl.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

Peter at Hyperlipid has gone into this subject, I'm having trouble finding the link. This study was in a list of studies related to a study he posted about sialic acid lack on the other side of the equation, in lesions in the artery wall, leading to the delivery of fat and cholesterol to the wound area.

So what depletes the sialic acid?

Thus, in the blood of over 95% of the CHD patients examined, we found a modified, sialic acid-poor form of LDL that determines the potential of a patient's plasma to cause lipid accumulation in arterial cells. Additional evidence indicating the presence of sialic acid-depleted LDL in the blood of CHD patients has recently been obtained. In these patients, we have found anti-LDL autoantibodies with much greater affinity for sialic acid depleted LDL than for native LDL or chemically modified LDL (28). This observation strongly suggests that desialylation is a significant LDL modification that occurs in vivo.

A vegan blogger might use this to peg red meat as the cause of heart disease. I am not a vegan blogger.

Most mammals make a type of sialic acid called Neu5gc. Humans can only make a precursor of Neu5gc called Neu5AC. Sialic acid is used as a marker-molecule in the immune system. The body develops anti-bodies to the Neu5GC.

http://www.telegraph.co.uk/science/science-news/3346666/Mystery-of-the-meat-eaters-molecule.html

Humans are weird. We don't make vitamin c; important to collagen formation. We don't make allantoin; which is oxidized from uric acid, (I'll post about that sometime) which is also important to collagen formation, both are important to healing, including broken arteries. One more weirdness; we don't make Neu5Gc, instead we have an immune reaction to it. Could all three of these be related?

The Neu5gc concentration is very low in most human tissue. The few places where it is high, the fetus, tumours, the gut-- are also the tissues with the most growth or turnover. So, if our mother eats red meat, we have lots of Neu5gc initially, but over time general maintenance weeds that out and replaces it with the stuff we make ourselves, the Neu5Ac.

A vegan blogger might tell you the Neu5gc finds its way into the tumour because meat causes cancer. I'm not going to tell you that. Maybe red meat also causes babies and intestines. But there are implications of that Neu5gc. If you're fighting cancer, for instance, cancer cells conveniently tagged with foreign sialic acid might come in handy to the immune response, especially if doctors find a way to take advantage of this.

Now, here's the question;

Is there something about Neu5Ac that makes it more prone to the degradation of its sialic acid? That isn't the question I thought I was going to ask. I'll go ahead and ask that question anyways; Is there something about the Neu5Gc that makes it prone to the degradation of its sialic acid? Or is there something about it that changes it's general distribution?

Given the known differences in sialic acid biology between humans and great apes (Varki 2008), we also stained normal-appearing myocardial sections from humans
and apes with two lectins that bind sialic acids: Sambucus nigra agglutinin (SNA) which recognizes terminal Siaa2-6Galb1-4GlcNAcb- units on N-linked glycan chains of glycoproteins, and Maackia Amurensis hemagglutinin (MAH), which recognizes Siaa2-3Gal termini on various glycoconjugates (Martin et al. 2002; Varki and Varki 2007). Both SNA and MAH strongly stained large areas of heart sections from chimpanzees, gorillas and orangutans, with MAH staining again showing evidence of encircling ‘bundles’ that were not seen in human heart sections (Fig. 4). These differences with SNA and MAH lectin staining imply that terminal sialic acids are much denser in the great ape heart.

http://cmm.ucsd.edu/varki/varkilab/A173.pdf

Varki should maybe read Hyperlipid. He (Varki) seems to think the purpose of the healing process in chimpanzees and in humans is to kill the subject. Chimpanzees and humans don't heal the same. So although both get heart disease, which is basically a mis-healing, it looks different.

Paraffin sections of hearts from humans, chimpanzees, gorillas, and orangutans were stained using the Masson-Trichrome stain for collagen. As shown in Fig. 3, otherwise normal heart sections from all three great apes showed collagen bundles that appeared to divide the heart muscle along the planes where the larger blood vessels were situated. This pattern was not observed in the human heart sections.

Okay. Another anomaly; missing collagen bundles. Humans are collagen-challenged. We can't make vitamin c or allantoin (not on purpose. uric acid can still oxidize into allantoin, but we lack the specific enzyme.)

Just in case I didn't actually say what I meant to say, here it is; unable to make vitamin c or allantoin on purpose, our collagen making ability is compromised. We need to somehow live in spite of this; something about our metabolism of sialic acid causes our damaged arteries to use material and energy from ldl cholesterol for repair. This keeps us from being dead.