Ketone bodies are an important energy source for our bodies during periods of fasting. They provide the brain, the myocardial muscles, and the skeletal muscles with energy whenever our body has to live off its reserves. The following article addresses the synthesis and degradation of ketone bodies, their impact on the pH-level of the blood as well as their clinical relevance with regard to diabetes—all of which is based on pre-med biochemistry knowledge.

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Image: “Circles” by Susanne Nilsson. License: CC BY-SA 2.0


Types of Ketone Bodies and Their Function

There are three substances in our body that are considered ketone bodies:

  • Acetoacetate
  • Beta-hydroxybutyrate
  • Acetone

Acetoacetate and beta-hydroxybutyrate are normal metabolic products of the liver whereas acetone does not have any function in our metabolism. Acetone is a product of spontaneous decarboxylation of acetoacetate and is disposed of with the respiratory air or in the urine.

Acetoacetate and beta-hydroxybutyrate are only synthesized in the mitochondrial matrix of hepatocytes. Brain, myocardial, and skeletal muscles all rely on the reconversion of these substances in times of low glucose levels.

Since the brain cannot use fatty acids for energy generation because the blood-brain barrier is not permeable to fatty acids, it is dependent on ketone bodies in periods of fasting as its sole energy resource. Using ketone bodies, the brain is able to reduce its glucose demand from an average of about 150 g/day to about 50 g/day.

Activation of Ketone Body Synthesis

From a biochemical perspective, ketone body synthesis will be reinforced whenever there is an increased presence of acetyl-CoA (the starting substance of ketone body synthesis), as is the case during longer periods of fasting or starvation.

Furthermore, diabetes mellitus causes an accumulation of acetyl-CoA: The lower insulin production or higher insulin resistance leads to an increase in the degradation of fatty acids which in turn leads to more acetyl-CoA being produced. Acetyl-CoA, however, can only enter the citric acid cycle if there is a sufficient amount of oxaloacetate available for the first reaction of the citric acid cycle. But with diabetes mellitus, the absorption of glucose from the blood into the cell is inhibited which leads to a reduced activity of glycolysis and thus a reduced production of pyruvate and oxaloacetate. This means that patients with diabetes have increased amounts of acetyl-CoA with a simultaneous deficiency of oxaloacetate—resulting in an intensified synthesis of ketone bodies.

Supply of Acetyl-CoA

Acetyl-CoA is the product of various metabolic pathways:

  • The degradation of fatty acids yields 1 acetyl-CoA with every cycle of beta-oxidation.
  • Glycolysis provides pyruvate as a primary product, which is decomposed into acetyl-CoA by pyruvate dehydrogenase or into oxaloacetate by pyruvate carboxylase to eventually enter the citric acid cycle.
  • Acetyl-CoA is also produced in the degradation of certain amino acids, which are accordingly called “ketogenic amino acids”.

Ketogenesis

Step 1

Initially, 2 acetyl-CoA are condensed to form acetoacetyl-CoA, catalyzed by the enzyme thiolase. In this step, one CoA is cleaved, which provides enough energy for the synthesis of the product.

Step 2

The next step, which is catalyzed by β-hydroxy-β-methylglutaryl-CoA synthase (HMG-CoA synthase), adds another molecule of acetyl-CoA to the beta carbon of the acetoacetyl-CoA by using water.

This step produces β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA), which is a branched 6-carbon compound and also an intermediate in the synthesis of cholesterol in the cytosol.

Step 3

One acetyl-CoA is cleaved by HMG-CoA lyase, which produces acetoacetate.

Step 4

Acetoacetate now can be reduced to D-β-hydroxybutyrate by D-β-hydroxybutyrate dehydrogenase in an NADH+H+-dependent reaction, or it may undergo spontaneous decarboxylation to form acetone.

Beta-hydroxybutyrate is the ketone body with the highest blood concentration during a persistent lack of food. Figure 1 summarizes the reactions of ketogenesis.

Ketogenesis pathway

Image: “Ketogenesis pathway. The three ketone bodies (acetoacetate, acetone, and beta-hydroxy-butyrate) are marked within an orange box” by Sav vas. License: CC0 1.0

Ketone Body Uptake

The ketone bodies thus formed travel through the bloodstream towards their target tissue. The brain is able to utilize ketone bodies with the assistance of monocarboxylate transporters (MCT).

These transporters are located, for example, in the plasma membrane of endothelial cells of astrocytes and neurons; they also organize the transport of lactate, which can be reduced to pyruvate. The uptake occurs through proton symport.

Ketone Body Utilization

Ketone bodies can be utilized in the entire body (especially the brain) except for the liver; for ketone bodies, the liver functions exclusively as a site of synthesis.

Step 1 and 2

In the first step of utilization, beta-hydroxybutyrate is—unless this has already occurred—oxidized to acetoacetate, the second most common ketone body in the blood. This is an NAD+-dependent reaction and catalyzed by beta-hydroxybutyrate dehydrogenase. Acetoacetate can now be activated to acetoacetyl-COA through either of two mechanisms:

  • The 3-ketoacyl-CoA transferase transfers the CoA-group of the succinyl-CoA (which is a by-product of the citric acid cycle) to the carboxyl group of the acetoacetate—which yields acetoacetyl-CoA as well as succinate.
  • Catalyzed by acetoacetyl-CoA synthetase, CoA reacts in an ATP-dependent reaction with the carboxyl group of acetoacetate, which forms water, ATP, and acetoacetyl-CoA.

Step 3

Now, the acetoacetyl-CoA is cleaved by thiolase with the use of one CoA to form two acetyl-CoA.

Acetyl-CoA is now available for energy production in the citric acid cycle and for the synthesis of necessary reducing equivalents to keep the respiratory chain running. Figure 2 shows the most important chemical reactions in the utiization process of ketone bodies.

Ketoacidosis

If the pH of the blood drops below 7.35, this is referred to as acidosis. Ketoacidosis is an acidosis caused by high blood concentrations of ketone bodies.

Since all 3 types of ketone bodies are acidic, they can cause a reduction of blood pH which can give rise to an acidosis. This is the reason why we may develop ketoacidosis when we are fasting.

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