Fats are bothered by fructose, not by glucose, that even protects against fructose!

And again, fructose! Sugar! White poison! Well, wait, maybe it depends on the situation. Let's look at an interesting study that examined the effects of fructose on the metabolism of mice. Animal models have the advantage that you have everything under control, so you can easily observe the mechanisms of how things happen.

We already know about fructose, it activates the processes of glycolysis of glucose to lactate to obtain energy without the need for oxygen. This is not always bad, sometimes it can be useful, sometimes not. With simple reasoning, we can directly deduce that fructose does not promote the oxidation of fats to ATP energy, because only glucose or some amino acids can be fermented. On the contrary, when there is an excess of glucose, fermentation to lactate can be useful because it relieves the mitochondria and helps reduce the level of glucose in the blood.

I mentioned the mechanism of increased lactate production in another post, see for yourself. What is interesting about the whole process of glycolysis, or the breakdown of glucose into pyruvate and eventually into lactate, is that glucose is converted into fructose after basic phosphorylation. Always. Fructose is, therefore, an absolutely essential metabolite and there is basically no reason why it should be a poison. It reminds me a bit of the thesis about the harmfulness of fats or cholesterol, also absolutely essential and irreplaceable metabolites.

But glucose is converted to fructose-1,6-bisphosphate (FBP). Fructose is converted to fructose-1-phosphate (F1P). It is not exactly the same molecule, but for some enzymes, it is a false substrate that attaches but does not work as well as FBP. So we described that fructose affects the enzyme PKM2 during mild hypoxia. What if it can also bind to other enzymes, such as aldolase. This is part of the detection of sufficient carbohydrates and this sensor controls the synthesis of fats from excess carbohydrates by the enzyme ACC. We know that fructose activates the synthesis of fats from glucose, so-called de novo lipogenesis (DNL). Nothing new.

So let's take a look at a study that investigated how the metabolism of mice can be influenced by drinking sweet water with glucose or sweet water with fructose. They also tested this on a standard mouse diet and a high-fat diet containing 60% of calories from lard.

Khk siRNA turns off fructose activation by the KHK enzyme. Cpt1a activates fat transport for burning, fructose suppresses it.

The first thing that caught my attention was this graph. To help you understand, fructose is activated by the enzyme KHK. If you turn this enzyme off, it's as if fructose wasn't there. In this graph, in the control group on a high-fat diet (HFD), turning off KHK caused a fundamental change in the expression of the enzyme that activates the transport of fats, especially long-chain fats, into the mitochondria. Without this enzyme, fats cannot get into the boiler, they cannot be burned. How is it possible that the control group without added fructose or glucose no longer allows for trouble-free fat burning? Well, just look at the methodology and it's clear, the researchers used the product D12492 as a high-fat diet. It is formulated so that mice gain weight really quickly. And to make it work like this, carbohydrates are enriched with sugar by one-third. A diet that appears to be fructose-free already contains about 3.5% of calories in the form of fructose. It's not much, but as we will see later, even such a small amount is essential, especially with fatty foods.

Here you can see how just 3.5% fructose in a high-fat diet (HFD/Cont) changes the profile of medium and dicarboxylic fatty acids compared to a fructose-free state (HFD/Khk). We know that MCT fats help, especially C8 and C10. Fructose somehow disrupts them.

This model is perfect for us because it clearly shows that a small amount of fructose can be neutralized with water sweetened with glucose/dextrose. Another picture shows that the acetylation of enzymes plays a crucial role. Glucose will help synthesize citrate in the mitochondria, and at the same time, glucose also activates the enzyme ACLY to convert citrate to acetyl-CoA in the cytosol. Among other things, glucose can also be used to ensure sufficient NADPH, which, as we already know, must not be missing, because its deficiency usually activates cellular senescence and inflammation. When burning fat, it is therefore important to maintain a high ratio between glucose and fructose. Even if carbohydrates are few, as in this case 20% of calories, if there is any fructose in the diet, there must be an estimated 10 times more glucose or starch. I don't know the exact number, from which ratio it is already okay, but obviously 5 times more glucose is not enough.

Malonyl-CoA suppresses the function of CPT1a in the last column; the positive effect of glucose (HFD+G) is clearly visible, and fats get into mitochondria. Fructose, even in minimal amounts (HFD) prevents this. At the same time, it is also seen how glucose added to a low-fat diet blocks fat burning by suppressing transport into mitochondria, fructose does not do this.

Let's now see if fructose is harmful even on a low-fat diet. If the diet contains 55% carbohydrates and 22% fat, fructose activates the formation of fats from glucose. And that is actually good because it will help remove glucose from the circulation and store it as fats. The only thing that needs to be taken care of is that these newly stored fats can be processed between meals. Here, we see that glucose deactivates the entry of fats into the mitochondria, while fructose does not.

What can I add to that? It is interesting how a very small amount of fructose is enough to disrupt fat burning on a high-fat diet. It seems to me that there must be many more such mechanisms; for example, the absence of medium and dicarboxylic fatty acids indicates that fructose probably suppresses omega oxidation of fats, i.e. the formation of dicarboxylic acids if burning fuel in the mitochondria is limited for some reason. Dicarboxylic acids are burned in peroxisomes and relieve overloaded mitochondria.

Free fatty acids (FFA) in the blood after an overnight fast, fats waiting to be burned. Fructose (F) increases re-storage, and glucose (G) decreases their burning. Chow 22% fat, HFD 60% fat in the diet

One more picture, in vitro verification. The combination of fat (FFA - oleate/palmitate) and fructose accumulates fat and depletes antioxidant protection, creating an acute NADPH deficiency. Increased glucose (25 mM) can replenish the missing NADPH and ensure the normal function of regulatory loops (antioxidant protection).

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