How to make fructose in the liver, but you better not do it!

In one of my previous posts, I looked at the work of Richard Johnson, who claims that we have something like a fat switch in our body. While it is turned off, the body works normally and burns fat. If you inadvertently turn it on, you will store more fat and burn less. We also learned from him that the easiest way to turn it on is to quickly flood the liver with sugars dissolved in water, ie with the help of sweet drinks.

If we start to look in more detail at what process we will actually start, we will find this interesting enzymatic pathway (production line), which resides in liver cells and other organs that have glucose intake independent of insulin levels. This enzymatic pathway can convert glucose, generally considered a good and harmless sugar, into fructose, which according to research is considered to be one of the causes of metabolic problems such as obesity, diabetes, heart attack, etc. It is called the polyol pathway.

Quotation from Wikipedia (you can skip it, if you want):

The polyol pathway is a two-step process that converts glucose to fructose.^[1] In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.

The pathway is implicated in diabetic complications, especially in microvascular damage to the retina,^[2] kidney,^[3] and nerves.^[4]

Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.^[5]

The polyol enzymatic pathway, it consumes NADPH, will reduce your production of reduced glutathione (a cellular antioxidant).

Cells use glucose for energy. This normally occurs by phosphorylation from the enzyme hexokinase. However, if large amounts of glucose are present (as in diabetes mellitus), hexokinase becomes saturated and the excess glucose enters the polyol pathway when aldose reductase reduces it to sorbitol. This reaction oxidizes NADPH to NADP+. Sorbitol dehydrogenase can then oxidize sorbitol to fructose, which produces NADH from NAD+. Hexokinase can return the molecule to the glycolysis pathway by phosphorylating fructose to form fructose-6-phosphate. However, in uncontrolled diabetics that have high blood glucose - more than the glycolysis pathway can handle - the reactions mass balance ultimately favors the production of sorbitol.^[6]

Activation of the polyol pathway results in a decrease of reduced NADPH and oxidized NAD+; these are necessary co-factors in redox reactions throughout the body, and under normal conditions they are not interchangeable. The decreased concentration of these NADPH leads to decreased synthesis of reduced glutathione, nitric oxide, myo-inositol, and taurine. Myo-inositol is particularly required for the normal function of nerves. Sorbitol may also glycate nitrogens on proteins, such as collagen, and the products of these glycations are referred-to as AGEs - advanced glycation end-products. AGEs are thought to cause disease in the human body, one effect of which is mediated by RAGE (receptor for advanced glycation end-products) and the ensuing inflammatory responses induced. They are seen in the hemoglobin A1C tests performed on known diabetics to assess their levels of glucose control.^[6]

While most cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney, and nervous tissues are insulin-independent, so glucose moves freely across the cell membrane, regardless of the action of insulin. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway. When blood glucose is normal (about 100 mg/dl or 5.5 mmol/l), this interchange causes no problems, as aldose reductase has a low affinity for glucose at normal concentrations.

In a hyperglycemic state, the affinity of aldose reductase for glucose rises, causing much sorbitol to accumulate, and using much more NADPH, leaving less NADPH for other processes of cellular metabolism.^[7] This change of affinity is what is meant by activation of the pathway. The amount of sorbitol that accumulates, however, may not be sufficient to cause osmotic influx of water.

NADPH acts to promote nitric oxide production and glutathione reduction, and its deficiency will cause glutathione deficiency. A glutathione deficiency, congenital or acquired, can lead to hemolysis caused by oxidative stress. Nitric oxide is one of the important vasodilators in blood vessels. Therefore, NADPH prevents reactive oxygen species from accumulating and damaging cells.^[6]

End of quotation from Wikipedia.

Let's review important information:

1. Activation of the polyol pathway deprives you of the main intracellular antioxidant (reduced glutathione, abbreviation GSH)
2. It will reduce the production of nitric oxide, so your blood vessels will not be flexible enough and the risk of high blood pressure will increase.
3. It will damage your thinnest blood vessels (capillaries) in your eyes and kidneys.
4. It endangers normal nerve function.
5. It causes protein glycation (something like roasting meat brown, but in your own body and more slowly).

So really nothing nice.

We will look for further context. I have stated in several previous posts that without reduced glutathione it is not possible to burn fats, they will be preferentially stored. By activating the polyol pathway, you also activate the production of fats from glucose, ie from common carbohydrates, from starch.

And now let's look at how this has to do with the issue of polyunsaturated vegetable oils. We will have to get bogged down in great detail, but don't worry, I will try to explain.

Obtaining cellular energy (ATP molecules) is a very complex process. There are basically only two sites where ATP arises from the ADP molecule. The first is in the cytoplasm without the presence of oxygen by the decomposition of glucose, fructose or galactose by so-called glycolysis, the second is in the mitochondrial enzyme complex V (five) which is the last electrical machine of the so-called electron transport chain, which processes electrons from NADH or FADH2.

Where do NADH or FADH2 molecules come from? They are a product of the so-called beta oxidation of fats or they can be a product of the Krebs (known also as TCA or citrate) cycle which is fed by intermediate products of decomposition of carbohydrates and fats. Fats do not allow to obtain ATP without the presence of oxygen, they do not have something like glycolysis in sugars.

And now for that context. Beta oxidation of fats is basically done by cutting off small pieces of a long chain fatty acid. This cutting of the two-carbon pieces takes place enzymatically, ie on micromachines specialized in this operation. But we already know that fats can have none, one, two or more unsaturated bonds in the chain, so it is necessary to have more options for trimming, more specialized enzymes. Different enzymes need different so-called cofactors to perform their function,

And here we come to the heart of the matter. While beta oxidation of saturated and monounsaturated fatty acids does not consume NADPH molecules, beta oxidation of polyunsaturated fats (vegetable oils from seeds) consumes NADPH. The fact that this causes a lack of reduced glutathione GSH is already known from other studies, it only confirms the validity of the hypothesis that the burning of polyunsaturated fatty acids in mitochondria or peroxizomes at least contributes to the epidemic of diseases of civilization. At the same time, NAD+ molecules are also consumed and NADH molecules are formed, but fewer FADH2 molecules are formed than in saturated fats, which can also have consequences. There is an excess of substrate for the production of ATP, but there is not enough signaling, there is not enough glutathione, this blocks the electron transport chain at the very beginning, on the first mitochondrial complex. And the second mitochondrial complex, which processes only FADH2 molecules, will also not work very well because not much FADH2 molecules is produced from polyunsaturated fats.

Beta oxidation of polyunsaturated vegetable oils consumes valuable NADPH molecules. In the picture beta oxidation of linoleic acid (omega-6).

Returning to the polyol enzymatic pathway, it also consumes NADPH molecules, so it causes a deficiency of reduced glutathione (GSH), this slows down the consumption of NADH and causes a deficiency of NAD+ molecules. The basic energy mechanisms of the cell, such as the Krebs cycle and the electron transport chain slow down or stop. Take a look to the numbered paragraph above. These are the problems caused by NADPH deficiency and NAD+ deficiency. Think about what the combination of both processes, burning polyunsaturated vegetable oils and consuming sweet drinks will do with the cell. It cannot end differently than problems and illnesses. And again, alcoholic beverages behave very similarly in metabolism, especially at higher doses. The combination of vegetable oils from seeds with sugars and sweet or alcoholic beverages will reliably destroy your liver and cause many other health problems.

I would like to add one more hypothesis. Maybe Richard Johnson and the other proponents of the theory of the dangers of fructose are slightly wrong. The problem is probably not fructose itself, nor glucose or carbohydrates. The very process of activating the polyol pathway can be a problem. Although it is activated by sugars, with a normal healthy diet, when the concentration of sugars sent to the liver does not exceed safe levels and when there is no dangerous reduction in NADPH or glutathione levels, sugars and carbohydrates do not cause any problems. However, these safe levels are likely to be greatly reduced by excessive consumption of polyunsaturated fats. This is because these processes compete for the same molecules, namely NADPH, and both processes simultaneously can cause its deficiency.

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References:

Polyol pathway

Fatty acid oxidation

The phosphate makes a difference: Cellular functions of NADP

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

2,4 Dienoyl-CoA reductase

Alcohol metabolism - Microsomal (Cytochrome P450) Oxidation of Ethanol