Does the ketogenic diet destroy the heart?

The ketogenic diet is based on the strict restriction of carbohydrates in the diet, quite popular now. There are groups of people in the world who strongly promote the ketogenic diet as a cure for obesity, type 2 diabetes and other diseases. The very first known and documented therapeutic use of the ketogenic diet is for childhood epilepsy. Since then, the number of diagnoses suitable for the application of a ketogenic diet has greatly expanded. Therefore, it is highly desirable to investigate how the composition of fats affects the effectiveness, but mainly the safety, of this diet. The main component of the ketogenic diet is fat. And there are many different types of fats from different sources. Some can harm, others help.

A ketogenic low-carbohydrate diet reduces body weight, MCT oils reduce the amount of adipose tissue, thus preserving more lean tissue.

Recently, a number of studies have been published showing the potential danger of heart damage on the ketogenic diet. Let's look at one of the more recent ones, which explores the possibility of eliminating the problems of the ketogenic diet by supplementing with medium-chain fats, that is, MCT oil containing C8:0 and C10:0.

SD - standard mouse diet, LCT - mainly long chain triglycerides (lard 66%, butter 8.8%, LA 6.4% by weight in the diet), LCT/MCT - 33% LCT replaced by medium-chain fats. Duration 8 weeks.

Fibrous heart tissue occurs with any ketogenic diet, it can cause heart disease, it is mainly caused by an increased content of 4-HNE. CR - calory restriction (80% of SD).

The study was conducted on mice, the composition of the diet was chosen as an 8:1 ketogenic mix, i.e. approx. 80% of calories from fat. In the abstract, we read that replacing a part of long triglycerides with medium ones could not prevent the formation of fibrous tissue caused by the oxidation product of linoleic acid (omega-6), i.e. 4-hydroxy-2-nonenal (4-HNE). It can therefore be concluded that even MCT oil cannot replace the exclusion of omega-6 sources from the diet. This is simply a necessary condition. No omega-6 fats, because mitochondrial metabolism of linoleic acid will deprive you of antioxidant protection. I've mentioned it here many times before. Safe fat burning absolutely needs quality cellular antioxidant protection, reduced glutathione (GSH). It cannot be supplemented from the diet, its destruction can only be prevented by excluding linoleic acid from the diet. An additional option is to minimize the damage caused by even a small amount of omega-6 by consuming omega-3, i.e. ALA (linseed) or DHA (fish oil). But even so, only small amounts should always be consumed. The protective effect of omega-3 fats lies in the partial diversion of fat burning to peroxisomes. This relieves the mitochondria and reduces omega-6 toxicity.

And as we will see in the ketogenic diet study, the diversion of combustion from mitochondria to peroxisomes is also responsible for the effects of MCT oil. The study does not say so, but it is clear from the results and graphs. One of the main manifestations of peroxisomal fat burning is the production of acetate, another manifestation is a decrease in the level of ketones (β-OHB), because these are created in the mitochondria. And both of these phenomena were clearly manifested. Why do MCT oils activate peroxisomal fat burning? Because they pass through the main limiter of fat burning, i.e. malonyl-CoA, a product of de novo lipogenesis (DNL), which blocks the entry of long fats into the mitochondria. This triggers the reaction, production of H2O2 and subsequent activation of omega fat oxidation. In this case, dicarboxylic acids are formed from fatty acids (including long saturated ones) by modification of the other end, which activate peroxisomes and are burned in them. This relieves the mitochondria. Similarly, omega-3 (DHA) relieves mitochondria. They activate the burning of omega-6 fats in peroxisomes.

If you are interested in the mechanism by which linoleic acid destroys the antioxidant protection of mitochondria, it consists in the high consumption of NADPH molecules. The enzyme 2,4-dienoyl-CoA reductase, which consumes NADPH, is used to break down unsaturated bonds in even positions. Other fats hardly need this enzyme, or are burned mainly in peroxisomes. Although this enzyme is also used there, it does not destroy the antioxidant protection. The high consumption of NADPH in mitochondria is manifested by a decrease in the restoration of oxidized glutathione to active reduced glutathione GSH. In this case, the main producers of NADPH are the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2) and the enzyme NNT. During its activity, the latter consumes the accumulated charge on the membrane for the production of ATP. It therefore reduces the available energy of ATP, consumes NADH, which is manifested in the cell plasma also by a lack of NADH, increases glycolysis and the availability of the competing fuel, pyruvate. At the same time, the level of acetyl-CoA in the mitochondria will also increase, leading to increased production of ketones. It's not good. This leads to the activation of PDK, i.e. the defense mechanism, preventing the entry of pyruvate into mitochondria by blocking pyruvate dehydrogenase and increased lactate formation. However, this can cause the activation of pseudohypoxia, i.e. glucose fermentation. The cell reacts in the same way as when there is a lack of oxygen. Mitochondrial overload can have unfortunate consequences, especially in tissues that fail to switch from fermentation back to oxidation, see older posts.

Acetate produced by peroxisomal fat burning will manifest itself in increased levels of acetylcarnitine. The latter is probably the main factor reducing obesity, it suppresses de novo lipogenesis.

Now let's get back to the ketogenic diet and heart health. 

4-hydroxy-2-nonenal (4-HNE), you really don't want that in your heart tissue.

An increased level of 4-HNE is a manifestation of increased consumption of omega-6 linoleic acid on a ketogenic diet. You can't fool the composition of fats. Even if you consume fats with a low omega-6 content, there will always be enough omega-6 for the production of 4-HNE. Therefore, I would add to the conclusions of the study, it is good to try to influence the activation of peroxisomes by the composition of the diet and reduce the oxidative stress of mitochondria on a fatty diet. MCT oils are one option.

Conclusions of the study:

"We conclude that despite normal ROS, cardiac tissue omega-6 FA availability results in low but constant 4-HNE production and the accumulation of 4-HNE protein adducts, leading to disrupted intracellular signaling and the observed fibrotic remodeling."

Another study conducted in rats specifies the cause of fibrotic changes in heart tissue directly to increased ketones, namely to β-OHB level and also reports the pathway, activation of the SIRT7 enzyme through suppression of histone deacetylase 2 (HDAC2). In addition, the activation of SIRT7 also reduces the biogenesis of mitochondria. All this with composition of the ketogenic diet containing only 4.25% soybean oil and 62.7% cocoa butter, i.e. only about 4% linoleic acid. This is a rather serious finding.

"Our results strongly suggest that unless the adverse effects of a KD on the cardiac system can be effectively avoided, healthy individuals should reconsider the use of a KD for weight loss."

Continue reading here.

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References:

Ketogenic diets composed of long-chain and medium-chain fatty acids induce cardiac fibrosis in mice

Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis