Ketone bodies are produced in the liver and then enter the blood. They are small and well soluble in water. This allows them to be wonderfully transported throughout the body. But how do the organs that normally burn glucose suddenly gain energy from ketone bodies?
In the last article, I introduced ketogenesis – the production of ketone bodies in the liver. You do not know yet? With a click on the link quickly read again! I’ll wait until then.
1. the liver cannot do anything with ketone bodies
The liver itself lacks a specific enzyme to produce energy from ketone bodies. 3-Keto Acid CoA Transferase is the name of the colleague. Going back to our theme park comparison, you can think of the liver as a specific park. There just aren’t the same attractions and roller coasters at Europapark as there are at Disneyland. Neither are the same employees. The liver is the European Park. The attractions are certain metabolic pathways and the employees the enzymes. If I really want to have an attraction from Disneyland, I can whine to the staff at Europapark for as long as I want, but it won’t help. I just have to go to Disneyland. And that’s what our ketone bodies think too. Europapark? No Disney castle? Well, then I’ll just get out of here. We’ve probably made the staff at Rust so angry by now that we’ll be kicked out anyway. And so the liver throws out the ketone bodies. Off into the blood.
2. ketone bodies are highly soluble in water
On the trip to Disneyland, the ketone bodies have a decisive advantage: they are traveling by car. This means that they can take the highway completely self-sufficient. From Rust to Paris. Others, like the fatty acids, have to wait for the bus first or spend way too much money on a cab. Ketone bodies are highly soluble in water, which is their car. Because fatty acids are not readily soluble in water, they need a means of transport. Their bus is the transport protein albumin. They are bound to these and can thus travel through the blood. Grease simply does not mix well with water.
3. if the ketone body concentration in the blood increases, it also increases in the organs
As soon as some ketone bodies are on the way in the blood, some press through the cell walls of the organs again and again. The more ketone bodies there are in the blood, the more crowded it becomes. They push and shove and more and more are pushed through the cell wall into the cells of the organs. The cells of the organs, such as muscles and brain, have not had such guests for a long time. Normally, they only get visits from glucose. At first, they don’t really know what to do with these strange ketone bodies.
10-20% of ketone bodies do not even make it to the organs. These are lost en route and are excreted in the urine. There is always a little shrinkage. Therefore, “ketosis” can be measured in urine.
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4. the organs must learn to burn ketone bodies
If you were handed an unusual vegetable – say okra – would you immediately know what to cook with it? Do not google!!! I guess not everyone would have an idea right away. But the more often you cook with okra, the better your dishes will taste with it. You learn to use the vegetables that were so foreign to you before. It is similar in the organs. In the beginning, they don’t really know what to do with ketone bodies. You could also say: Disneyland suddenly has a particularly large number of visitors from the land of Okra. Unfortunately, none of the staff speaks okra. First, the employees can only guide their guests into the attractions with hand signals. The theme park needs to hire competent employees who understand the language of the new guests. It takes time to hire enough Okra-speaking staff to competently serve all ketone bodies.
The right enzymes must first be formed in the organs to break down ketone bodies. Slowly but surely, the degradation is going better and better. The trigger for the formation of new enzymes are the ketone bodies themselves. Just as at Disneyland, Okrarians were the catalyst for hiring Okra-speaking employees.
5. ketolysis is ketogenesis backwards. Almost!
In ketogenesis, the production of ketone bodies, the ketone bodies were produced from crushed activated fatty acids (acetyl-CoA). During ketolysis, the breakdown of ketone bodies, they become acetyl-CoA again. This enters the so-called citrate cycle (also known as the Krebs cycle or citric acid cycle), where it is completely broken down into its individual components. Energy is generated in the process. The energy is stored in the form of ATP. This is the universal energy currency of the body. Something like the euro for Europe. Don’t worry, it works fine in the body!
(The body has namely understood that energy can always be transformed only from another form. Energy cannot simply be created, cannot be manufactured anew. Energy inflation does not exist).
6. 3 enzymes are needed for the degradation of ketone bodies
First, the ketone body 3-hydroxybutyrate must be converted back into acetoacetate. The canoe just magically changes shape again. You can read again how acetoacetate became 3-hydroxybutyrate in the article“How are ketone bodies formed?“. If these mind games are too colorful for you, and you would rather have serious science, then scroll down a little further. Below the picture you will find the biochemical processes explained again seriously in scientific language.
You are still here? Well then, the colorful mind games continue for you for now:
The worker responsible for this magical conversion (the enzyme) is 3-hydroxybutyrate dehydrogenase. Subsequently, the employee 3-keto acid CoA transferase activates the acetoacetate. It turns on the switch, so to speak, of the acetoacetate canoe tandem. It then becomes acetoacetyl-CoA, the activated form of acetoacetet. It seems to me that the ketolysis staff are all too good for nicknames. Too bad actually.
In ketogenesis, after all, two canoes were connected to form a canoe tandem. Here, at ketolysis, the two canisters are now separated again. Now we are back to the individual canoes, acetyl-CoA. The worker/enzyme acetoacetyl-CoA thiolase is responsible for this step. As already mentioned, this enters the citrate cycle and energy is extracted from it.
7. this complicated process is a clever move
Okay, so what’s the point of all this effort? First, fatty acids are released from the adipose tissue into the blood, then they are converted into ketone bodies in the liver. However, the liver cannot do anything with the ketone bodies and therefore throws them out again. Via the blood, they reach the muscles, brain and other organs. There, the ketone bodies are broken down again and converted into energy. Can’t we save this act and directly burn the fatty acids in the organs?
The answer is “well”. The muscles burn fatty acids to some extent. However, as written above, these are not very soluble in water and must therefore be transported bound to albumin. The transport capacity is limited. The brain cannot use fatty acids at all because they do not pass through the blood-brain barrier. Ketone bodies, on the other hand, can pass the blood-brain barrier.
In times without food, the body of our ancestors had nothing but its fat reserves. Since the brain could not use them directly, the “detour” saved us. The brain had a fuel at its disposal that you always had with you. Ketone bodies obtained from body fat.
I’ll explain in the next article exactly how the brain uses ketone bodies, how it changes its metabolism and how effective the whole thing is.
Now follows a biochemical scheme with the described metabolic pathway, followed by the “serious” description of the processes and the source reference.
8. ketolysis in extrahepatic organs
The hepatocytes themselves cannot utilize the ketone bodies – they lack the enzyme 3-keto acid-CoA transferase – which is why the ketone bodies are released into the blood. While fatty acids are not water-soluble and are therefore transported bound to albumin in the circulation, ketone bodies are readily water-soluble. AcAc and 3HB diffuse into extrahepatic tissues along their concentration gradient and the rate of their oxidation in tissues is directly proportional to their concentration in blood. Nevertheless, 10-20% of ketone bodies in ketogenic metabolic state are excreted in urine. During ketolysis, the ketone bodies are converted back to acetyl-CoA, which then enters the citrate cycle and is completely oxidized. In this process, the oxygen consumption per mole of ATP produced is lower than in the complete oxidation of glucose.
For metabolization, 3HB must first be converted back to AcAc. The reaction is catalyzed by 3-hydroxybutyrate dehydrogenase, as was previously the case for interconversion in the liver. Subsequently, 3-ketoacid-CoA transferase activates AcAc to acetoacetyl-CoA.
Acetoacetate + Succinyl-CoA → Acetoacetyl-CoA + Succinate
This is followed by the cleavage of acetoacetyl-CoA into two molecules of acetyl-CoA by acetoacetyl-CoA thiolase.
Acetoacetyl-CoA ↔ 2 Acetyl-CoA
Like ketogenesis, ketolysis is localized in the mitochondria. The resulting acetyl-CoA is oxidized to H2OandCO2 in the citrate cycle. The “detour” of fatty acid oxidation via ketone bodies costs additional energy, but it is a way of transporting the energy content of the fatty acids from the liver to extrahepatic organs by a water-soluble route. The main reason may be that ketone bodies are the only alternative energy source to glucose for the brain during periods of food deprivation.
Ketone bodies can be metabolized by numerous organs including the brain, heart, and skeletal muscle, with ketolysis in the brain being quantitatively the most significant and best studied.
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Sources and interesting literature:
Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF. 1969. liver and kidney metabolism during prolonged starvation. J Clin Invest, 48(3): 574-583.
Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF. 2001. ketone bodies Potential Therapeutic Uses. IUBMB life, 51(4): 241-247.
Stipanuk MH, Caudill MA. 2013. biochemical Physiological and Molecular Aspects of Human Nutrition. Third ed. Philadelphia: Elsevier Saunders, 379-381.