Does potassium control testosterone secretion?

To recap; we have five senses of taste. Sweet, sour, bitter, salty and umami.

Insulin associates with the sense of sweet and regulates glutamine.

Leptin associates with the sense of umami and regulates glutamate.

Amylin associates with the sense of sour and regulates lactate.


So we're down to salty and bitter. Let's do salty next.

The obvious choice for a nutrient that the salty receptors are particularly attuned to is sodium, but I believe this is a modern distortion, and that potassium is the nutrient involved here.

L. Frassetto, R. Curtis Morris, Jr. and A. Sebastian did a study where they supplemented the diets of postmenopausal women with potassium bicarbonate.

http://jcem.endojournals.org/cgi/content/abstract/82/1/254


The theory is that the acid/base balance of the body determines protein wasting; when the system is less acidic, less nitrogen is lost in the urine. I've been doubtful about this study's results, more nitrogen might have been lost in the stool, but I now find myself less skeptical.

What causes an increase in muscle mass? Ask a bodybuilder, he'll know. Testosterone.


http://sciencelinks.jp/j-east/article/200707/000020070707A0256523.php

We report for the first time that supraphysiological concentrations of
testosterone induces relaxation in RA. This response may occur in part via
ATP-sensitive K'+' channel opening action

Now, there is nothing new about the idea that testosterone activates potassium channels. So what does that mean? Testosterone regulates potassium.

Here's another, don't believe me, believe this;

http://www.jstage.jst.go.jp/article/jphs/103/3/103_309/_article

We report for the first time that supraphysiological concentrations of
testosterone induces relaxation in RA. This response may occur in part via
ATP-sensitive K+ channel opening action.

If potassium is regulated by testosterone, doesn't it then make sense that rising levels of potassium will increase testosterone levels?


I have to warn here about the dangers of potassium-loading. Testosterone regulates potassium for a reason; in excess, this stuff is extremely dangerous.

Here's a little proof. I saw better proof a few years ago, in a study where rat pups were rendered potassium deficient. They failed to produce potassium.


http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T03c

Amelia Sánchez-Capeloa,
Asunción Cremadesb,
Francisco Tejadab,
Teodomiro Fuentesb
and Rafael Peñafiel, a
aDepartments of Biochemistry and Molecular Biology, University of
Murcia, 30100 Murcia, Spain
bDepartments of Pharmacology,
Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
Received 2
August 1993;
revised 8 September 1993.
Available online 14
November 2001.

Abstract
Potassium deficiency produced different effects in the kidney of male or female mice. While in female, potassium deficiency caused a marked renal hypertrophy with no significant changes in testosterone-regulated enzymes, such as ornithine decarboxylase and β-glucuronidase, in the male the same treatment provoked a marked fall of these enzymes owing to a dramatic decrease in plasma testosterone. Potassium replenishment restored plasma testosterone and renal enzymatic activities. These results show for the first time, that potassium modulates circulating
testosterone and suggest that this cation could exert an important regulatory
role in controlling androgen actions

Again, potassium deficiency causing testosterone secretion to decrease in male animals. Female animals proper hormonal balance involves less testosterone secretion than males does; the lower potassium intake in this study was more within their homeostatic range, so that the effect on testosterone in the female mice was lessened.

Again, anybody reading this do not I repeat do not potassium-load. Include foods that are not potassium depleted (that is, non-refined foods) in your diet. If your testosterone levels are low, it seems to me that you may be potassium-deficient.

Salty, potassium, testosterone. Looks like we're down to bitter.

This is getting a little silly

http://www.jbc.org/content/279/14/13393.abstract

This response to amino acids was decreased by 60% when glutamine was omitted. Insulin release by SUR1–/– islets was also stimulated by a ramp of glutamine alone.

In normal islets, methionine sulfoximine, a glutamine synthetase inhibitor,
suppressed insulin release in response to a glucose ramp.

High glucose doubled glutamine levels of islets.

Glutamine has been found to induce "insulin resistance" in fat cells.

Muscle cell glutamine production is increased by insulin.

Suppressing glutamine synthesis suppresses insulin release in response to glucose.

Insulin regulates glucose indirectly. Glutamine production decreases availability of glutamate, which reduces availability of glutamate-derived metabolites necessary to mitochondrial respiration. Less fat is fed into the kreb's cycle, increasing the cell's dependence on fermentation of glucose for energy, which increases the demand for glucose. Remember how exercise can increase glucose uptake without increased insulin? This is apparently why. And they did the study in 2004.

For proper symmetry, I guess it will be necessary that leptin increases the production of glutamate.

No wonder insulin is anabolic. It spares proteins from mitochondrial respiration (krebs cycle)

Methionine sulfoximine inhibition of glucose stimulated insulin secretion was
associated with accumulation of glutamate and aspartate.

I should say that insulin is expressed by the beta cells in reaction to glutamine to facilitate its uptake. Insulin will increase the demand for glutamine in any cell. If pre-made glutamine is not present, the demand for glutamine will be served by the synthesis of glutamine from glutamate. Sometimes I talk right around my main point.

Add on;


I went back and reread that glutamine inducing insulin secretion study, and they mentioned this;


http://content.nejm.org/cgi/content/full/338/19/1352?ijkey=523a998947f513e19c80d3216f3446ce60d9eb4f


"Hyperinsulinism and Hyperammonemia in Infants with Regulatory Mutations of the Glutamate Dehydrogenase Gene"


Glutamate dehydrogenase is an enzyme needed to convert glutamate to alpha-keto glutarate, which feeds into the kreb's cycle, and is thus needed to burn fat.


Lets see. Glutamine induces insulin secretion (And insulin induces glutamine production). Excess of an enzyme that breaks glutamate down into alpha keto-glutaric acid induces insulin secretion.
It almost looks like the lack of glutamate induces insulin secretion.

The control of GDH through ADP-ribosylation is particularly important in insulin-producing β cells. Beta cells secrete insulin in response to an increase in the ATP:ADP ratio, and, as amino acids are broken down by GDH into α-ketoglutarate, this ratio rises and more insulin is secreted. SIRT4 is necessary to regulate the metabolism of amino acids as a method of controlling insulin secretion and regulating blood glucose
levels.

So what would glutamine do? Spare glutamate, so that it can be made into alpha-keto glutarate?

More alpha keto glutarate. Does the Kreb's cycle use more alpha keto glutarate when glucose is providing acetyl coa? Like, the clock runs faster?

'Tis a slippery beast. Insulin appears to regulate glucose. But not really. Appears to regulate glutamine. But that might just be because glutamine spares glutamate so it can be broken down to alpha keto glutarate.

So it actually appears to create a demand for alpha keto glutarate, and glucose and glutamine merely facilitate this; except that muscle cells produce glutamine in reaction to insulin....

Okay. Muscle cells are pretty heavy on protein. Insulin might stimulate glutamate production from glutamic acid, at the same time providing substrate for both alpha keto glutaric acid and glutamine.

I'm sort of tied in knots.

But I think the proper way of looking at this is probably that insulin doesn't actually try to "regulate" anything. It's probably all about equilibrium, anyways.

Amylin; the pyruvic acid regulator

My work on leptin raised an obvious possibility. There are five tastes, umami, sweet, bitter, sour and salty. Leptin goes with glutamate, umami. Insulin with sweet, obviously. Are there other hormones corresponding to flavours? That might give a clue to their importance to whole-body homeostasis.

After a while it occurred to me that Amylin, which is the peptide that accumulates in amyloid plaque in the pancreas of people with type 2 diabetes, and in the brain of people with alzheimers, appears to sensitize people to leptin. Dr Bernstein gives amylin to some of his patients in order to decrease appetite for glucose. Now, does that sound familiar? So although amylin isn't technically a hormone, it seemed a likely candidate for a third taste related hormone-like substance. This Stephanie Steneff article gave me the information that I needed.

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

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.

I thought lactic acid was the significance of sour because of this. But then I realized that since amylin facilitates pyruvic acid breakdown into lactate, it must be secreted instead in response to the presence of pyruvic acid.

Once you look at it that way, something becomes obvious. The beta cell secretes insulin in response to glucose. It does this for the same reason that a yeast cell does; to get and use glucose. Beta cells are so bad at this that they provide enough insulin to service the needs of the entire human body.

Following this line of reasoning, it makes sense that excessive amounts of amylin would be produced or secreted when large amounts of pyruvic acid are present. The amylin facilitates the use of pyruvic acid for energy. (The actual amount of pyruvic acid needed to cause this amyloid production overshoot would depend on the level of resistance in the alpha cell, where amylin and glucagon are both produced.)

So the amyloid plaque in type 2 diabetes and alzheimer's starts to look like the signature of a bloom effect. Large amounts of glucose must have been broken down to pyruvic acid, spurring excess amylin production. The cells aren't intelligent; just like yeast cells, they have no idea that the high levels of pyruvic acid aren't forever, so they overproduce in anticipation.

Now, this is important; why would large amounts of pyruvic acid form? One possibility is that a local energy crisis has occurred, forcing cells to turn to the fermentation of glucose for a quick source of energy. This would lead to large amounts of pyruvic acid in the area. After which large amounts of amylin production overshoot would make sense.


What would cause the cells to turn to glucose fermentation? In cancer cells, it has been suggested that a local lack of oxygen might cause this. This makes obvious sense, fermentation is anaerobic.

Another possibility occurred to me, again thanks to Stephanie Stennef's article. You can't ferment fat; a local lack of free fatty acids might cause the excess fermentation of glucose that leads to pyruvic acid formation and high-gear amylin release. Animals that burn more fat for energy vs sugar live longer, this crosses many animal species.

Niacin, vitamin D, and a low carb diet done properly can raise adiponectin levels. Adiponectin lowers glucose production in the liver. What lowers glucose production? Our old friend physiological insulin resistance. When free fatty acids (particularly palmitic acid) enter the cell and feed into the Kreb's cycle, cellular energy needs are met and the need for glucose is reduced.

Increased fatty acids should make the fermentation of glucose to pyruvic acid less necessary and therefore no amylin overshoot should occur.

It seems likely that when blood levels of free fatty acids are high, the probability of cells needing to turn to glucose fermentation to meet their energy needs becomes much lower. This has obvious implications to the development of cancer.

That leads to thinking about what happens besides cancer when levels of free fatty acids are low. If a yeast-like bloom can occur when free fatty acids are not present, (fat acting as a control-rod of glucose and glutamate metabolism is another way to look at physiological insulin resistance), then tissues that are in greater than usual need of energy should be more susceptible to damage.

Tissues that are healing, for instance.

Adiponectin decreases the risk of heart disease and atherosclerosis. Most of the nutrients that Dr Davis at HeartScan Blog advocates to reverse plaque increase adiponectin levels.


More free fatty acids, lessened likelihood of a disrupted energy supply. A problem in this is that Type II diabetics often have higher than usual levels of free fatty acids in their blood. But they also often have compromised, undersized mitochondria; this could force them to turn to glucose when energy needs are high. I think this free fatty-acid "paradox" has thrown conventional science way off-track.

Once you're thinking lack of energy, compromised repair you think; cavities, bone loss, sarcopenia or muscle loss. All of the western diseases showed up together. It makes sense that they might have a common cause. Are we falling apart because we're not putting ourselves together?

Notice that Amylin, by helping to break down pyruvic acid to lactate, which can itself be metabolized, also may decrease glucose metabolism. When this is happening just a little bit more, not pathologically localized like in type II diabetes or in Alzheimers, insulin levels should be reduced, triglyceride synthesis should be lowered, and as a consequence more free fatty acids should be available to be oxidized.

The case for leptin as a regulator of glutamic acid metabolism

http://ajpregu.physiology.org/cgi/content/full/293/4/R1468

My first clue that leptin might be a regulator of glutamate metabolism came from this study;

Protein appetite is increased after central leptin-induced fat
depletion

Leptin reduces body fat selectively, sparing body protein. Accordingly, during chronic leptin administration, food intake is suppressed, and body weight is reduced until body fat is depleted. Body weight then stabilizes at this fat-depleted nadir, while food intake returns to normal caloric levels, presumably in defense of energy and nutritional homeostasis. This model of leptin treatment offers the opportunity to examine controls of food intake that are independent of leptin's actions, and provides a window for examining the nature of feeding controls in a "fatless" animal. Here we evaluate macronutrient selection during this fat-depleted phase of leptin treatment. Adult, male Sprague-Dawley rats were maintained on standard pelleted rodent chow and given daily lateral ventricular injections of leptin or vehicle solution until body weight reached the nadir point and food intake returned to normal levels. Injections were then continued for 8 days, during which rats self-selected their daily diet from separate sources of carbohydrate, protein, and fat. Macronutrient choice differed profoundly in leptin and control rats. Leptin rats exhibited a dramatic increase in protein intake, whereas controls exhibited a strong carbohydrate preference. Fat intake did not differ between groups at any time during the 8-day test.

Leptin seems to decrease appetite in rats only until fat mass is depleted. After that, appetite returns, and is similar in calories to non-leptin treated animals, but food preference changes to protein from carbohydrate in comparison to control rats. This suggests that rather than regulating calories, it regulates appetite for protein. In a similar way, insulin infusions will increase the appetite for glucose.

Now, glucose tastes sweet, so I wondered if there was a particular taste associated with leptin. I was looking for a protein taste, so umami seemed like a likely possibility. And umami is specific to glutamate.

So I needed a study showing the secretion of leptin in reaction to proteins. And I found it in this;

Regulation of leptin secretion from white adipocytes by insulin, glycolytic
substrates, and amino acids

The aim of the present study was to determine the respective roles of energy substrates and insulin on leptin secretion from white adipocytes. Cells secreted leptin in the absence of glucose or other substrates, and addition of glucose (5 mM) increased this secretion. Insulin doubled leptin secretion in the presence of glucose (5 mM), but not in its absence. High concentrations of glucose (up to 25 mM) did not significantly enhance leptin secretion over that elicited by 5 mM glucose. Similar results were obtained when glucose was replaced by pyruvate or fructose (both 5 mM). L-Glycine or L-alanine mimicked the effect of glucose on basal leptin secretion but completely prevented stimulation by insulin. On the other hand, insulin stimulated leptin secretion when glucose was replaced by L-aspartate, L-valine, L-methionine, or L-phenylalanine, but not by L-leucine (all 5 mM). Interestingly, these five amino acids potently increased basal and insulin-stimulated leptin secretion in
the presence of glucose.

Unexpectedly, L-glutamate acutely stimulated leptin secretion in the absence of glucose or insulin.

Finally, nonmetabolizable analogs of glucose or amino acids were without effects on leptin secretion. These results suggest that 1) energy substrates are necessary to maintain basal leptin secretion constant, 2) high availability of glycolysis substrates is not sufficient to enhance leptin secretion but is necessary for its stimulation by insulin, 3) amino acid precursors of tricarboxylic acid cycle intermediates potently stimulate basal leptin secretion per se, with insulin having an additive effect, and 4) substrates need to be metabolized to increase leptin secretion.

Various proteins stimulate leptin secretion in the presence of insulin or glucose. But only glutamate was found to stimulate leptin in their absence. This makes glutamate an excellent candidate for the protein regulated by leptin. The effect of other proteins on leptin secretion is likely an artifact of their interaction with glutamate.

Glutamate metabolites feed into the krebs cycle at several points. Fat cannot be metabolized for energy without this cycle, which explains the apparent control by leptin of appetite which disappears once fat is depleted. This is clearly true.


Poorly-regulated glutamate causes excitotoxicity in the brain, killing neurons. This is a protein needing careful regulation. The possibility that some disregulation of leptin/glutamate metabolism is involved in some neuro-degenerative disorders seems obvious.

Various proteins stimulate leptin secretion in the presence of insulin or glucose. But only glutamate was found to stimulate leptin in their absence. This makes glutamate an excellent candidate for the protein regulated by leptin. The effect of other proteins on leptin secretion is likely an artifact of their interaction with glutamate.Glutamate metabolites feed into the krebs cycle at several points. Fat cannot be metabolized for energy without this cycle, which explains the apparent control by leptin of appetite which disappears once fat is depleted. This is clearly true. Poorly-regulated glutamate causes excitotoxicity in the brain, killing neurons. This is a protein needing careful regulation. The possibility that some disregulation of leptin/glutamate metabolism is involved in some neuro-degenerative disorders seems obvious.

Notice that fat consumption was no different in the leptin-treated rats than in the control mice in that first study. This is because leptin does not directly regulate fat.

Also notice that although the two sets of rats were in drastically divergent hormonal states, they still took in the same number of calories. My guess would be that this has more to do with the amount of work being done in the body than anything else. Matt Stone may have a point; if the body expresses hunger, something, somewhere needs doing. I would disagree with him that calories matter in this; appetite, and the senses, should be trusted. We've forgotten how to trust all of our senses. That's why nobody seems to notice anymore when they make a major nutritional scientific breakthrough.

We really need to live in the real world.

Roaming Brownouts

http://journal.shouxi.net/qikan/article.php?id=412025

Snell Dwarf mice burn more fat, less sugar when at rest.

Do the modern diseases of civilization have a common cause? Is this cause a series of roaming brownouts, energy shortages throughout the body? Wear exceeds repair, and the repair that is done is shoddy.

This could show up in a number of areas, including;

1 tissue that receives relatively little blood flow.

2 tissue in higher than usual need of energy for repair. Such as the arteries, especially at main branching points.

3 tissue with very high energy needs at the best of times, such as the brain.

There is strong evidence that increased energy from fatty acids vs. glucose use during fasting increases the lifespan, this crosses a wide number of species. I see longevity as the fight against entropy. Things last longer if kept in better repair. Interventions that increase HDL and lower triglycerides in humans also raise free fatty acids, which induces physiological insulin resistance.

Which should also have the obvious effect of lessened disruption of the delivery of the energy needed for proper maintenance and repair to high-need tissues with less disruption. I see the possibility of a condition similar to a bloom in yeast, depleting blood of nutrients in a very localized hypoglycemia. Measuring blood sugar doesn't tell you what is happening in a very acute area.

Perception and sense and nutrient partitioning.

In a fairly recent study on mice of the C57BL/6J strain, a very curious thing happened. Restricting mice to ninety-five percent of the calorie intake of control mice, the result was that the restricted mice became much fatter, with less lean mass than the control mice.

http://www.nature.com/oby/journal/v18/n3/full/oby2009312a.html


The authors of the study put it this way;

Mild CR altered body composition, energy expenditure, and meal patterns in female C57BL/6J mice. The increase in fat and decrease in lean mass may be a stress response to uncertain food availability.

A stress response to uncertain food availability. The control mice were given unlimited access to food. An all-you-can-eat buffet. The calorie-restricted mice only ate slightly less food than the control mice, but the control mice were given the opportunity to eat way more food. The mouse's body somehow reacted to the perception that food was limited by a shift in body mass away from lean tissue and protein storage and towards the storage of fat in adipose. This is a sensible adaptation if winter or a dry season, anything that would cause a prolonged food-shortage, is coming. And it illustrates a point; how the animal perceives the food is an important determinant of the fate of that food in the body. You might argue that these are special, genetically inbred mice; this doesn't matter to human obesity. But when we look at the extremes, certain things become obvious. That is the real value of studies in genetically-modified mice.

The mice saw, and smelled and ate less food. But these are not the only ways that animals metabolisms sense food. In the stomach and digestive track, there are numerous receptors, some of them similar to the taste receptors on the tongue. So even after an animal has eaten, signals are being sent, the nutrients being digested are "perceived" by the metabolism. That isn't all that's being perceived; the gut is full of bacteria, these bacteria put out various products that interface with various gut receptors.

Germ free mice fed a diet that causes mice with a normal gut bacteria culture to grow fat, fail to become obese.

The trillions of microbes that colonize our adult intestines function collectively as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. Given the worldwide epidemic in obesity, there is interest in how interactions between human and microbial metabolomes may affect our energy balance. Here we report that, in contrast to mice with a gut microbiota, germ-free (GF) animals are protected against the obesity that develops after consuming a Western-style, high-fat, sugar-rich diet.

http://www.jstor.org/pss/25426219

Metabolome refers to the complete set of small-molecule metabolites (such as metabolic intermediates, hormones and other signalling molecules, and secondary metabolites) to be found within a biological sample, such as a single organism.

That's from wikipedia. So the study authors are writing about the interplay of various hormones and molecules. This is certainly going on. I think just as important to a discussion of what goes on in germ-free mice is the effect of bacteria on the metabolism's sense of the nutritional environment. Do you have a bad cold? Tongue all covered with microbial-rich white stuff? How does this affect your taste of smell? I think that it's reasonable to at least conjecture, from the information presented so far, that something akin to this may be taking place in the gut; as a clean tongue without visible buildup gives a clearer sense of taste, a clean gut should improve the body's ability to sense the nutrients present in the gut. This should make the dance between nutrition and metabolism go that much smoother.

http://docnews.diabetesjournals.org/content/4/4/6.full

It is tempting to think that the interplay between our native metabolism and our gut bacteria is one way-- bad gut bacteria are to blame for our obesity. But it doesn't necessarily work that way. The following is from an article in DOC (diabetes, obesity and cardiovascular disease) news.

Gordon's team initially identified a link between gut microbiota and the amount of energy mice harvested and stored from food. The team observed that conventionally raised mice—those harboring microbiota since birth—had 42% more total body fat than comparable mice raised in the absence of microorganisms. This held although the conventional mice consumed about 29% less chow than the germ-free mice. When the researchers colonized distal intestine microbiota from the conventional mice to the germ-free mice, the previously lean germ-free mice increased body fat by roughly 60% in just 14 days.

See? Those darn bacteria made those poor rodents fat, even though they ate less, not more, food than the germ-free mice. A fecal transplant from control to germ-free mice corrected for this patent inequity.

But wait. Further on in the same article;

During their analysis of the gut microbial community structure of two mice sets from a common mother, researchers led by microbial ecologist Ruth Ley found differing proportions of two principal groups of gut bacteria most commonly associated with mammals, including humans, in the obese and lean mice. One set was genetically obese because of a leptin gene mutation, while the other was lean, carrying either a single copy or no copy of this mutation. Despite having the same diet, obese mice had a 50% higher representation of the gut bacterium Fermicutes and a proportionally lesser representation of the bacterium Bacteroidetes than the lean mice.

Notice that these are genetically obese mice, suffering from the consequences of a leptin gene mutation. We are not helpless against our bacteria; I find it hard to look at the above paragraph without seeing a certain amount of regulation of the gut bacteria population by the hormone leptin. The firmicute bacteria that are more common in obesity may worsen obesity; but many of them may only be present because of an hormonal imbalance. The effect of leptin will be modulated by all the other hormones, as well. So, once again by looking at an extreme, we have learned a basic principle; gut bacteria population is strongly influenced by the host. How does leptin regulate gut bacteria? One likely mechanism would be by affecting nutrient availability; individual species of microbes tend to lean very heavily on particular nutrients, some prefer glucose, some certain proteins, glutamate for instance, etc. Glutamate may be pivotal in all of this, or at least one of several key pivots, which I'll go into later.

Gut bacteria ferment carbohydrates and proteins, and various fibers; this alters availability of nutrients to the host. So by interacting with the gut bacteria by hormonally altering their nutrient availability, the host in effect alters the nutrients which will be absorbable by the host itself. The host is not totally defenseless against the environment, and that includes the interior environment. There are certainly environments to which the host is incapable of adequate adjustment, outside of the host's homeostatic range of metabolic adaptation. But it does what it can. Implanting gut bacteria from obese mice to germ free mice makes the mice obese, bacteria from lean mice keeps them lean. Perhaps the bacteria from the obese mice simply present the previously germ-free mice with an internal environment which is outside of their proper homeostatic range; perhaps some nutrient is provided to the host in greater or lesser supply, or perhaps the nutrient sensing by taste receptors in the gut is altered.

Let's look at another interaction between animal and environment, the effect of calorie-restriction. Calorie restriction is well known to increase lifespan across a wide range of animals, from mouse to monkeys. There are caveats; death rates early in life often increase. But the animals who survive this early danger tend to live much longer than controls. I see this as another artifact of the interface between environment including food, and metabolism.

From Science Daily, april 20, 2007;

Changes caused to bugs in the gut by restricting calorie intake may partly explain why dietary restriction can extend lifespan, according to new analysis from a life-long project looking at the effects of dietary restriction on Labrador Retriever dogs.

Them crazy gut bacteria at work again.

More;

The scientists believe that differences in the makeup of gut microbes between the two sets of dogs could partly explain their metabolic differences. The dogs that were not on a restricted diet had increased levels of potentially unhealthy aliphatic amines in their urine. These reflect reduced levels of a nutrient that is essential for metabolising fat, known as choline, indicating the presence of a certain makeup of gut microbe in the dogs. This makeup of gut microbes has been associated in recent studies with the development of insulin resistance and obesity.

So again, we have gut microbe environment affecting whole-body homeostasis. That leptin would only have some sort of interplay with gut bacteria in mice, and that leptin is the only hormone that does so, seems unlikely. Life is largely based on repeating themes, a simple strategy that is once successful will tend to reoccur again and again. This is of great help when trying to understand this sort of study.



We see choline-wastage in this study. And the dogs get fat. Choline is useful to metabolize fat. Might the dogs have a limited ability to "steer" the gut bacteria away from the type of bacteria that destroy the much-needed choline? The calorie-restricted dogs may have merely been within the limits of their proper metabolic range, compared to the ad-lib fed dogs. Alternately, the dog's limit for choline uptake may simply have become saturated.

One thing about this study, it's not just about calorie restriction it's also about food selection; without a control dog population that self-selects its own nutrients (which can be frightening in a lab), we can't know how much the results are an artifact of a difference in calories, and how much is caused by effectively tieing one arm of the dog's metabolism behind it's back, so to speak. Perhaps a non-calorie restricted dog would simply eat more choline, or more or less of some other element of the diet and thus avoid ill-health.


A key principle of calorie-restriction theory is "hormesis," which refers to an adaptation in an animal's gene expression, in reaction to some stress which is put on the organism. Calorie restricted animals are generally leaner, have longer maximum lifespans, prolonged breeding capability, and less cancer. But stress is just one of many inputs; again we return to taste, smell, sight, perception of food availability (although this counts as stress), the effect on gut bacteria population and the range of the animal's metabolism's ability to adjust to and to adjust its environment that includes those gut bacteria and the their effect on the general environment of the gut through the fermentation process. This must be true, otherwise the sense of taste, smell and all of those gut receptors are without purpose.

Okay. So. You're a mouse.

Suppose you're a mouse. You skitter around in the forest, nibbling at leaves, twigs, bugs-- whatever catches your fancy. You're lean and strong, and healthy. You do not have heart disease, your teeth aren't falling apart, your bones are strong. Good for you.



Now be a different mouse. The scientists have gotten a hold of you, fed you various chows with different mixes of fat, carbohydrate, protein and other nutrients which science has learned are essential to good health. They want to know what these various nutrients do in the body, how they interact, so they constantly manipulate and take notes. These scientists are studying the effect of certain foods on your body's metabolism; nutrition. At least, they might think that that's what they're doing. The reality is quite different, nutrition is a much slippier subject than most people imagine.



Be one more mouse, before I go into a little review of various actual mouses and other lab animals. Be an X-mouse, a mutant mouse altered by scientists to study the effect of genetics on body weight, lifespan, and disease. You may be altered to be particularly susceptible to heart disease. Then they can feed you various pelleted chow-type diets, with different ratios of various different nutrients, and see what the effect of those nutrients is on the progression of the disease. This is hopelessly complex. If you look at humans and protein alone, you can see how complex this really is. There are eight essential amino acids, and a number of conditionally essential amino acids, as well as numerous types of fat, and sugar. The possible dietary combinations are endless. Let's not kid ourselves. This appears to be beyond human comprehension. We may get clues from the mice in the studies that will help to decipher various disease processes, but we will never be competent to steer this machine.

Because that's what it's all about. Wild animals live in all kinds of constantly shifting environments. They run around eating. If food is plentiful, instead of growing obese and getting heart disease, they increase in population. This is what we see, so it is reasonable to believe that this is the case, although the picture is horribly incomplete. This is a cruel process; many of the young, often most, will be killed and eaten. Perhaps this is how homeostasis is achieved. Only the strong survive, survival of the fittest, and all that. Competition limits the availability of food, so the animals do not get fat.



The truth is that the interface between food and animal is an intricate hormonal dance. This is an even greater complexity than the problem with the large number of variables in nutrition itself. Insulin, growth hormone, testosterone, estrogen, amylin, glucagon, leptin, the list goes on and on and scientists haven't even completed that list, they're still discovering new hormones and peptides and enzymes. How are we to steer this thing?



The answer is of course that we are not. The mouse in the forest has absolutely no idea of nutrition. Instead, the mouse has an interface with reality, in the form of all of its senses, and especially in its senses of taste and smell. The mouse lives in the real world. We've forgotten how to do that.

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.