Are carbohydrates toxic?
In an older post, I focused on what to eat, what is probably harmful to us and, above all, in what quantity. I used the information here from Paul Jaminet's book Perfect Health Diet. In the section on carbohydrates, it states that the recommended maximum amount of carbohydrates is 150 g (600 kcal). Why? What happens in the body when the daily intake of carbohydrates is higher?
So let's investigate. First, let's look at this image from a study examining changes in metabolism in humans with varying amounts of carbohydrates and fat consumed, which I've added a little.
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| The picture shows the dependence of DNL on energy intake, CH=carbohydrates, P=proteins, fat intake does not affect this process. Empty bars show continuous process, full bars when eating. |
What do we see here? The process of de-novo lipogenesis (DNL), i.e. the formation of fats from glucose, is a natural protection against high carbohydrate intake. The total amount of fat thus produced in the liver or adipose tissue is relatively small, a few grams per day. Compared to the amount of fat consumed, it is negligible.
So what's the problem?
In the very start of the process of de-novo lipogenesis!
It's quite a complicated matter, I'll try to explain it with this doodle.
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| Explanations: H .. NADH, + .. NAD+, PH .. NADPH, P+ .. NADP+, G .. glucose, P .. pyruvate, AcCoA .. acetyl-CoA, C .. citrate, aKG .. 2-oxoglutarate , Glm .. glutamine, BOx .. beta fat oxidation, M .. malate, OxA .. oxaloacetate, A .. aspartate, blue schizoid .. mitochondria, FAS .. fat synthesis (sorry for the design, but this is more authentic) |
The process of making new fat from glucose or glutamine needs two things, citrate molecules and NADPH. That is all. Then it needs the activation of the right enzymes, specifically ACC1, i.e. acetyl-CoA carboxylase. Citrate, created by combining acetyl-CoA with oxaloacetate in the mitochondria, passes through its inner and outer membrane and is split again into acetyl-CoA and oxaloacetate with the help of the ACLY enzyme. Acetyl-CoA ends up in new fat and oxaloacetate is used to generate NAD+ to continue glycolysis. Citrate can also be used to produce NADPH, i.e. as energy source for fat synthesis. The result will be C16:0 molecules, i.e. palmitate, a saturated fatty acid. Part of them will be further extended and part desaturated, so that an optimal ratio for attachment to glycerol can be created and a fat suitable for storage in fat droplets, triglyceride (TAG triacylglycerol), will be created.
The whole problem is further complicated by the fact that permeation through membranes takes place via antiporters. Citrate must be paired with malate (red pathway) and 2-oxoglutarate with aspartate (yellow pathway). So if we need to get citrate out of the mitochondrion, an equivalent amount of malate will enter it. Similarly, if we want to get another 2-oxoglutarate into the mitochondrion, an equivalent amount of aspartate will leave it. Complicated? Yes, I'm simplifying as much as possible for understanding, I'm sure I'm missing a lot of things, there are more transport options through the membrane, I could be wrong.
Now let's imagine a normal situation without fat formation, glucose will produce pyruvate and NADH during glycolysis. NAD+ is used up and needs to be replenished. If we have enough glucose and little fat, we will also have enough NADPH from the PPP pathway. I marked this NADPH with a red circle (PH), it blocks both IDH1 and ME enzymes in the cytoplasm, there is no need to consume citrate or malate to produce NADPH. The citrate level stabilizes at a certain level and no more citrate is needed, the route highlighted in red stops. But we need cytosolic NAD+, so we convert aspartate to malate and back in the mitochondria via the so-called malate-aspartate shuttle. We gain NADH for oxidation but deplete NAD+ for the TCA cycle. This also stops glycolysis. For the system to start up, we have to consume some energy, it takes pyruvate and the malate-aspartate shuttle restores exactly as much NAD+ as is needed, the system itself regulates glycolysis as needed. In addition, it is regulated by citrate, which also regulates glycolysis. Perfect system.
Let's change the environment now, we will have low glucose and high fat. How will it manifest itself? Without glucose, there will be little NADPH. The brake marked with a red wheel will not work. We need to replenish NADPH with citrate or malate. Both paths are used as needed. Let's assume we don't make any new fat. We need oxaloacetate from citrate to restore glycolysis, but we have nowhere to send acetyl-CoA. There is no interest in him. This path will be blocked and the NAD+ will not recover. But one can restore NADPH with IDH1 by making 2-oxoglutarate from citrate and reverse the direction of mitochondrial IDH2, this will make both NADPH and restore NAD+ via the aspartate-malate shuttle. And you don't even need oxygen for that. Citrate can be used to restore NADPH in a fatty environment at the cost of slowing or stopping the TCA cycle.
Let's try to make NADPH from malate. We remove aspartate from the mitochondrion, so 2-oxoglutarate enters the mitochondrion (as glutamate, yellow route). If citrate cannot go out (that is, if NADPH cannot be regenerated via citrate), malate cannot enter the mitochondrion either (red route) but it can produce pyruvate and NADPH (purple route). This is great because pyruvate enters the mitochondria and can be converted to either oxaloacetate or acetyl-CoA, both of which will be used. Further oxaloacetate is obtained via TCA from 2-oxoglutarate (glutamate), glycolysis can proceed.
But we have little glucose and a lot of fat, so NADH in the cytoplasm is converted to NADPH by ME and NAD+ in the mitochondria run out. The process can only continue after some NADH has been burned. The system is regulated as needed. But there is one catch, it cannot be done without the consumption of the amino acid glutamine, from which we obtain 2-oxoglutarate and glutamate, a high consumption of glutamine could limit the TCA cycle. But there is also a lack of cytosolic NADH, which protects against the activation of pseudohypoxia in a fatty environment and thus protects the cell against epigenetic changes caused by activation of HIF-1α.
And now we're just getting into what the activation of lipogenesis will do with a higher glucose intake in fat-free environment. Let's try to remove acetyl-CoA. Thus, oxaloacetate is released. Citrate will not continue towards IDH1 to 2-oxoglutarate on the right side (we have a lot of NADPH). The resulting oxaloacetate continues on the left side and is converted to malate and NAD+ to continue glycolysis. At the same time, the malate-aspartate shuttle runs to transport NADH to the mitochondria and control glycolysis. More malate enters the mitochondrion, allowing the output of citrate for fat formation. 2-oxoglutarate does not enter and yes aspartate does not exit, the amino acids glutamate or glutamine are not burned. No poisonous ammonia is produced.
So DNL works best without burning fat. It allows the anaerobic storage of new fat made from glucose and the continuation of glycolysis without pseudohypoxia, lactate is not formed, and glutamine is not consumed.
But it is worse when fat production is activated in an environment with enough fat. Beta oxidation of fats via the aspartate-malate shuttle blocks glycolysis, excess NADH is converted to NADPH and consumed via reversing IDH2, finally consumed to make fats from proteins (glutamate, glutamine) and cytosolic NADPH made by IDH1. The reverse running of IDH2 stops the TCA cycle, the incoming malate through the reverse running of SDH produces succinate and activates HIF-1α, i.e. pseudohypoxia. What was needed for that? ACC1 activation in a high NADH environment from fat beta oxidation. Fat burning alone is not enough, lack of cytosolic NADH would prevent pseudohypoxia. ACC1 must also be active, which activates the glutamine pathway towards citrate. New fats are formed mainly from amino acids.
High ACC1 activity is a consequence of low AMPK activity. Acetate, when activated to acetyl-CoA, can activate AMPK. Fat burning needs acetate, which activates AMPK to turn off ACC1. Acetate is a product of peroxisomal oxidation of either dicarboxylic acids formed by omega oxidation of saturated fats or alpha linolenic omega-3. It is also produced by the activity of bacteria in the digestive tract. If there is not enough acetate / propionate / butyrate in the cell, metabolism will be depressed, the TCA cycle will stop and hypoxia will occur.
Paradoxically, energy and material from beta oxidation of fats in mitochondria or in peroxisomes can also be used for fat formation, while peroxisomes can stop beta oxidation of fats in mitochondria by consuming NAD+. This can protect the mitochondria from damage. Activation of peroxisomes by means of PPAR-γ activates the formation of fats, i.e. precisely this metabolism that activates the problematic consumption of glutamine. This changes the pH of the cell by releasing ammonia, poisoning the mitochondria and triggering pseudohypoxia. In contrast, activation of PPAR-α without PPAR-γ does trigger fat formation, but safely with enough acetate, i.e. without burning glutamine and without DNL.
Conclusion:
So, what is the answer to the original question? Are carbohydrates toxic?
As such, carbohydrates are not toxic unless they are burned with fat (< 10%). If fats are also burned, this leads to the burning of proteins, specifically the amino acid glutamate or glutamine. It is the result of fat burning during activated de-novo lipogenesis. Carbohydrates, proteins and fats are therefore involved in this process. If de-novo lipogenesis is activated by high carbohydrate intake, it is not good to burn fat at the same time. It's either or. If we want to burn fat, then the intake of carbohydrates must be small enough not to trigger lipogenesis, i.e. up to 150g. The analysis also suggests that turning off ACC1, i.e. de-novo lipogenesis, can prevent glutamine burning so that pseudohypoxia is not activated as a solution to low pH problems.
Supplement
I also found a preprint in which the authors looked at liver cells, measured metabolic fluxes and investigated the connection between DNL and glutamine metabolism.
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| Metabolic Complementation between Glucose and Amino Acid Drives Hepatic De Novo Lipogenesis and Steatosis |
Note:
Personally, I think that even IDH3 (dependent on NADH) can work in reverse when IDH2 (dependent on NADPH) is impaired and can therefore consume NADH directly. This would explain the very low level of NADH in IDH2 genetically disabled mice on a high-fat diet
References:
https://perfecthealthdiet.com/
Chapter Eight - Antiporters of the Mitochondrial Carrier Family
Causes and Consequences of A Glutamine Induced Normoxic HIF1 Activity for the Tumor Metabolism
Amino Acids as a Primary Carbon Source in Hepatic Lipogenesis
Fasting induces hepatic lipid accumulation by stimulating peroxisomal dicarboxylic acid oxidation
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