Sunday, February 03, 2019

Lactate as bulk energy transport

Using RQ to track whole body substrate oxidation is pretty straight forward. An RQ of 1.0 means glucose oxidation and of 0.69 indicates fat oxidation. Mixtures come out in between. It is very simple to show that glucose is routinely converted to fatty acids because in the immediate post prandial period for any rodent fed standard low fat crapinabag the RQ becomes greater than 1.0. We would expect that during the later period when the rodent is asleep/not eating there would be a lower than expected RQ (lower than the calculated food quotient, FQ) while predominantly stored fat is oxidised. But on a high carb, very low fat diet we would expect the overall averaged RQ over 24h to be a little under 1.0, ie pretty much the same as the FQ. For an hypothetical "all glucose" diet part of the glucose diverts thus via fatty acids:

Eating: Glucose minus a little O2 -> fat      RQ > 1.0

Sleeping: Fat plus lots of O2 -> CO2 + H2O    RQ < 1.0

CO2/O2 = 1.0 on average over 24h.

If that 24h averaged RQ was all we had to work with we would not suspect that de-novo lipogenesis ever occurred. Nice and simple.

Much more difficult to pick up is the bulk conversion of fatty acids to glucose. This produces an unusually low RQ in the short term. But if the glucose is being produced to fuel the brain during starvation then its prompt oxidation would "correct" the unusually low RQ back upwards to a fatty acid RQ. The obvious exception was noted in a metabolically fat adapted and lactating young lady during extended fasting. She made glucose and galactose from fatty acids and gave them to her baby, rather than oxidising the sugars herself. End result was an RQ of 0.454 after just over three days of fasting with continued breast feeding.

She was making sugar out of fatty acids in bulk. She might or might not have been doing the same without lactation but in the absence of donating the sugars to her infant this would never show.

So the RQ and the FQ always average out to be the same unless something very specific is happening, ie as with Martha.

Much more difficult is to ask how do you tell whether glucose is being converted to pyruvate which then enters the mitochondria to join the TCA or whether glucose converts to lactate which is then shipped in to the mitochondria. And what if you have the absolutely crazy idea that glycolysis almost always leads to lactate and that this lactate is a transferable currency between cells? Glucose is then viewed as a one way gift from liver to tissues, to be shared out between cells/tissues as lactate.

That latter view has to use tracers to look at lactate or glucose flux. Label some lactate with carbon-13 and infuse it to steady state in the plasma of a mouse. Kill the mouse promptly and humanely and look where the C-13 atoms have ended up in glycolysis and/or TCA intermediates. Repeat the process with C-13 labelled glucose. Then glutamate. And then any other intermediary metabolite which might remotely shift bulk energy around the body.

It turns out that in starch fed mice glucose and lactate are the bulk plasma energy carriers, lactate slightly more so than glucose in the fed state and much more so in the fasted state. Certainly on a molar basis, bearing in mind that a mole of glucose has twice the carbon of a mole of lactate, which makes the situation slightly more complex. But lactate labels the TCA more strongly than glucose. Not surprisingly glucose labels glycolytic intermediates better than lactate.

Free fatty acids and ketones are a separate subject in high carbohydrate/low fat fed mice but they flux remarkably little energy, at least when fasting is limited to eight hours. Brain metabolism is also another separate subject.


Glucose feeds glycolysis to lactate. Most of this glycolytic lactate enters the plasma pool. Plasma lactate feeds the TCA in other cells.

Now the insightful bit from near the end of the letter:

"Among the many metabolic intermediates, why does lactate carry high flux? Lactate is redox-balanced with glucose. The rapid exchange of both tissue lactate and pyruvate with the circulation may help to equate cytosolic NAD+/NADH ratios across tissues, allowing the whole body to buffer NAD(H) disturbances in any given location. Nearly complete lactate sharing between tissues effectively decouples glycolysis and the TCA cycle in individual tissues, allowing independent tissue-specific regulation of both processes. Because almost all ATP is made in the TCA cycle, each tissue can acquire energy from the largest dietary calorie constituent (carbohydrate) without needing to carry out glycolysis. In turn, glycolytic activity can be modulated to support cell proliferation, NADPH production by the pentose phosphate pathway, brain activity, and systemic glucose homeostasis. In essence, by having glucose feed the TCA cycle via circulating lactate, the housekeeping function of ATP production is decoupled from glucose catabolism. In turn, glucose metabolism is regulated to serve more advanced objectives of the organism".

What I think this is saying is that lactate supplied to the TCA/OxPhos is for "housekeeping" ie ATP production. Glycolysis is for anabolism. Neither is absolute, but I find it an interesting point of view.

So the ultimate TLDR is:

Ox-phos = housekeeping
Glycolysis = anabolism

There is probably significant fudge-room.



Tucker Goodrich said...


raphi said...

"The rapid exchange of both tissue lactate and pyruvate with the circulation may help to equate cytosolic NAD+/NADH ratios across tissues, allowing the whole body to buffer NAD(H) disturbances in any given location. Nearly complete lactate sharing between tissues effectively decouples glycolysis and the TCA cycle in individual tissues, allowing independent tissue-specific regulation of both processes"

Isn't that just the so-called Reverse Warburg-Effect?

"Ox-phos = housekeeping
Glycolysis = anabolism"

Looks like that to me. More ammo for Seyfried

Peter said...

raphi, I have a paper somewhere which suggested that phospho-enol pyruvate was the transformation factor between rapid cancer growth and reversion to a more benign phenotype. But they had to use an "in their lab only" three dimensional cell culture technique, so this needs a major replication effort, which seems unlikely to be easily done...

I can't really see this as a black and white scenario, a thyroid adenoma is very different from a thyroid carcinoma. I followed some of the cell lines used in this paper back to see how aggressive the original in-vivo tumour was in the patient who started a given cell line. I was "fascinated", if that is the word, by the poor prognosis for people with anaplastic** thyroid cancer, which has a completely non functional complex I in the cell line. The term* "bloody 'opeless" springs to mind!


*The late LC Vaughan who tried to teach myself and the rest of my year some surgery in the 70s. "In these days of guarded prognosis, the prognosis is not just guarded, it's bloody 'opeless". Broad welsh accent required. Stuck with me!

** Anaplastic is a word you never want to see on a path report.

Peter said...


Peter said...

oops, sorry raphi, wrong paper. Can't find the one I want at the moment. Will try later


Peter said...

raphi, try this one. You might like it.


Peter said...

It is the one I was looking for BTW.

Puddleg said...

This ties in with something I read in a textbook (on google books) about glycogenolysis and liver zoning;
Glycogen is stored in parenchymal cells in deep liver zones supplied with blood lower in 02.
The first step of glycogenolysis is anaerobic - conversion to lactate.
The lactate is then taken up by hepatocytes in more oxygenated liver zones and converted to glucose.
Presumably anaerobic glycogenolysis in the low 02 zones supplies the ATP needed to make fresh glycogen when glucose reappears there in quantity.

Peter said...

George, yes, my feeling is that this sort of interplay will be going on all over the body, except, apparently, within the brain.


altavista said...

It's a lot more complex than this unfortunately.

"in the presence of physiological albumin, we found that cultured
murine PDAC cells grow indefinitely in media lacking single essential amino acids"

The methods seem legit, but then I don't know my aminoacids well.

Peter said...

altavista, interestingly pancreas and pancreatic cancer were the most glutamine fluxing of all of the tissues/tumours looked at in the paper. I doubt anything is simple!!


altavista said...

I think because they exhibit stronger hypoxia than the others?

"Strikingly, under conditions of hypoxia or defective mitochondrial function, glutamine can become the major source of lipogenic acetyl-CoA through reductive carboxylation"

Does keto have an impact on glutamine? If not, are the neoplastic cells really stressed out by Seyfried/Warburg?

Eric said...

Unrelated, just wanted to let you have this little gem:

Eric said...

Even more unrelated:

Eric said...
This comment has been removed by the author.
karl said...

Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways

But - what if most cancers are really about dysfunctional MT? (They don't respond well to the extrinsic pathway for apoptosis from the immune system). If they are using the cell-wall to produce energy - blood sugar matters - out growing the immune system? If lactate is a trans cell energy carrier - this gets more complicated.

Of course both narratives might be true - or not.

RE - the OT Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1

First - I am reluctant to trust any paper on Statins - politically toxic - distorted by grant money - but - if I take this paper on face - if the upside is better heart muscle at the expense of skeletal muscle - what happens to BG? Cancer rates? Then there is the bit "quercetin prevented this deleterious atorvastatin effect" -- trouble is in the weight lifting community, people have figured out that antioxs can block muscle gain.. and 25 mg/kg/day is a lot! I see they posted no conflicts, yet the atorvastatin was supplied free by Pfizer. It is interesting that people are starting to see ROS as a signal --

Further OT: Kendick was shooting fairly close at the CTT (from Oxford) - if what he insinuates is true - and the CTT has a monopoly on holding the data - it could explain why the down side is hard to get a handle on. I don't like monopolies - they hurt the public. Statins do fit the junk science pattern where the effect keeps diminishing over time (and disappears in research not run by Pharma)

Peter said...

atavist, I think that protein intake might just have some influence on glutamate supply. Not all of us favour 1.6g/kg/d!

Eric, I’ve had that paper for some time, it might get a post. The cat is amazing, hope it makes it. We had a near drowning in iced water to resuscitate years ago, it had some neuro probs afterwards, can’t recall the long term outcome.

karl, the paper on statins is interesting in how it is constructed. I think the the whole “opposite effect in skeletal muscle vs cardiac muscle” is incorrect. Looks more like depleting CoQ generates RET. Just a little will multiply mitochondria (which will also be CoQ depleted by the statin). A lot will produce myopathy. They compared “normal” cardiac muscle with/without statin against “myopathic” skeletal muscle vs non myopathic muscles, presumably all on a statin. The table S2 is a dud link. No huge surprise they are opposite. As you say, it’s a statin paper, it will be bent.


G. L. said...

Dr. Kwasniewski says something that perhaps you can clarify. It is at the end of his letter/answer to someone. This is using Google Translator. (I don't read Polish).

"Bronchial asthma.

The heart is the biggest when it has to burn glucose in the process of glycolysis, smaller when it has to process glucose in the so-called pentose pathway, smaller when it needs to burn ketones and free fatty acids, and the smallest when it does not burn anything and all the energy needed to he obtains his work from active phosphate compounds, mainly from ATP. It is "electric" energy coming from batteries. After the energy from ATP is taken up by the brain and heart, the compound is sent back to the liver, exercised muscles and other tissues, recharged and the cycle repeats hundreds of thousands of times a day. ATP itself manages daily body 50-100 kg, depending on the weight of the body and the intensity of the effort, especially mental, but also physical. And other active phosphorus compounds (accumulators) are produced in the human body a dozen or so.

And they are also used as sources of clean energy. With intense mental work, ATP levels in brain tissue are rapidly declining, and biochemists, physiologists and physicians continue to claim that glucose is the only source of energy for the brain, and in the absence of glucose, ketone bodies can cover up to 75%. brain demand for energy.

Glucose is not burnt in the brain at all. It is transformed into NADPH a key compound needed for almost all syntheses and for pentoses, i.e. compounds (sugars) necessary for the construction of many structures in the body. They are a component of nucleic acids (DNA, RNA), structures responsible for inheritance and for all electromagnetic communication between cells, organs and environment, they are needed to build many enzymes and numerous glycoproteins, ie protein-sugar compounds - pentoses such as ribose, ribulose, arabinose, xylose, lysosose, xylulose. Without these sugars, pentoses (five-carbon sugars), there would be no life on Earth.

When the body needs more pentoses or NADPH, more carbohydrates are directed to processing in the pentose pathway, which is not beneficial for the body. With the best model of nutrition, the body performs the least "stupid" work and is the slowest to remodel. Once it adapts to Optimal Nutrition, it does not have to adapt to other products, it does not have to lose energy, NADPH and - pentoz.

Therefore, in people using Optimal Nutrition, so-called basic metabolism is the smallest compared to all other nutrition models, and it should be that way, and it's good.

"Dorodna" - means the so-called grown-up youth is a very bad result of nutrition, which forces the synthesis of larger amounts of NADPH or pentozes, a lot of unnecessary work, acceleration of maturation and menopause and leads to a significant reduction in the duration of human life.