Energy metabolism Part 12: Ketone body metabolism
By now, you all’ve probably heard about the ketogenic diet.
A ketogenic diet is a very low-carbohydrate, high-fat diet.
This diet triggers the metabolic fasting state of the body.
During longer fasting periods, fatty acids are broken down to ketone bodies in the liver
and are readily available to other tissues.
Extrahepatic cells, with the exception of erythrocytes, can use ketone bodies as an
alternative energy source.
Ketone bodies are water-soluble, energy-rich compounds that are easily transported across
cell membranes.
They include acetoacetate, β-hydroxybutyrate, and acetone.
Actually, from a chemical perspective, β-Hydroxybutyrate is not a ketone but an alcohol.
However, it can be easily oxidized to acetoacetate and is, therefore, considered a ketone body.
Ketone bodies are only formed under special circumstances: The first requirement is glucose
deficiency.
This can be a physiological state resulting from low glucose availability that affects
the entire body, for example, due to fasting.
Alternatively, this state can be due to a pathophysiological condition like diabetes
mellitus, in which cellular glucose uptake is inhibited, causing intracellular glucose
deficiency.
In this case, to supply extrahepatic tissues that can’t break down fatty acids, the liver
switches to gluconeogenesis and the breakdown of fatty acids.
For this breakdown, beta-oxidation splits fatty acids in the liver into acetyl-CoA.
Usually, the acetyl-CoA is further metabolized in the citric acid cycle.
Conversion of acetyl-CoA to ketone bodies in ketogenesis only starts when there’s
a relative deficiency of oxaloacetate in addition to low glucose levels.
This causes the citric acid cycle to come to a standstill.
Two factors are responsible for this relative deficiency: Low glucose levels inhibit glycolysis
so almost no pyruvate is available for forming oxaloacetate.
Also, fatty acid degradation results in the accumulation of acetyl-CoA.
Therefore, the amount of acetyl-CoA far exceeds the amount of oxaloacetate available to the
citric acid cycle.
Although oxaloacetate is formed during the enhanced gluconeogenesis, it’s primarily
metabolized to glucose in this pathway.
So, relative deficiency of oxaloacetate means: an insufficient amount for the current demand.
Now, let’s take a closer look at the ketogenesis processes.
During ketogenesis, two molecules of acetyl-CoA are initially converted to acetoacetyl-CoA.
The reaction is catalyzed by the enzyme thiolase.
In the next step, a third molecule of acetyl-CoA is used to convert acetoacetyl-CoA to HMG-CoA.
The enzyme responsible for this reaction is HMG-CoA synthase.
Afterwards, HMG-CoA is transformed into the ketone body acetoacetate by HMG-CoA lyase,
cleaving acetyl-CoA from the molecule.
So, to yield one molecule of acetoacetate, a total of two molecules of acetyl-CoA are
required.
β-Hydroxybutyrate is then formed by reducing acetoacetate, with this reversible reaction
catalyzed by β-Hydroxybutyrate dehydrogenase.
The liver doesn’t use ketone bodies for its own energy supply but releases them into
the blood.
This way, they reach extrahepatic tissues, especially the cells of the brain, cardiac
and skeletal muscles, and the renal cortex.
If a cell requires energy, it absorbs ketone bodies from the blood, which are then converted
back into two molecules of acetyl-CoA during ketogenolysis.
These molecules can enter the citric acid cycle, as there is no oxaloacetate deficiency
in extrahepatic tissues.
This way, acetyl-CoA contributes to the generation of ATP in these cells.
The first enzyme involved in ketogenolysis, thiophorase, is only present in extrahepatic
tissues.
This ensures that ketone bodies aren’t broken down again into acetyl-CoA in the liver, where
they’re formed.
Thiophorase activates acetoacetate to acetoacetyl-CoA.
The enzyme responsible for the next step is thiolase, which we’re familiar with from
ketogenesis and beta-oxidation.
In ketogenolysis, it catalyzes the formation of acetyl-CoA.
So we see that only acetoacetate and β-hydroxybutyrate are important for energy metabolism.
The third ketone body, acetone, isn’t metabolized.
Like β-Hydroxybutyrate, acetone is formed from acetoacetate.
Though, the decarboxylation reaction is spontaneous, or, in other words, not catalyzed by an enzyme.
So, acetone is excreted as a metabolic end product in exhaled air.
If larger amounts of acetone are produced, this can even be noticed by its distinct smell.
Clinically, ketogenesis plays a role in, for example, type 1 diabetes mellitus.
It can cause a dangerous condition through the following: Due to the intracellular deficiency
of glucose, the concentration of ketone bodies in the blood increases, resulting in a drop
in serum pH below 7.3.
The drop is caused by acetoacetate and β-hydroxybutyrate, which both possess an acid group that cleaves
its proton under physiological conditions.
Ketoacidosis is defined by a low serum pH and high levels of ketone bodies in blood
and urine, which can be measured in a diagnostic laboratory.
Furthermore, the fruity odor of acetone in the breath and Kussmaul breathing are hints
of diabetic ketoacidosis.
Acidosis can also cause vomiting, while hyperglycemia can lead to osmotic diuresis, resulting in
large losses of electrolytes.
In severe cases, coma can occur.
If you’d like further information on diabetic ketoacidosis, check out the article containing
all the important information on its pathophysiology, diagnosis, and treatment.
Let’s sum up the most important aspects mentioned here on ketogenesis:
The three ketone bodies are acetoacetate, β-hydroxybutyrate, and acetone.
During ketogenesis, ketone bodies are formed from acetyl-CoA in the mitochondria of hepatocytes.
Acetyl-CoA arises mainly from the breakdown of fatty acids.
The liver doesn’t metabolize ketone bodies but produces them primarily for cells in the
brain as well as skeletal and cardiac muscles.
In ketogenolysis, ketone bodies are converted back into acetyl-CoA, which is fed into the
citric acid cycle and used for ATP synthesis.
The body has no use for acetone.
It’s excreted primarily via the lungs.
Were you able to remember all the important aspects mentioned on ketone bodies?
Let’s see if you have in the quiz on the next slide.