Ketone bodies metabolism

By: Cristhian Camilo Lozano Fernández

Abstract

Ketone bodies are the water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and the
spontaneous breakdown product of acetoacetate, acetone) containing the ketone group that
are produced by the liver from fatty acids during periods of low food intake (fasting),
carbohydrate restrictive diets, starvation, prolonged intense exercise, alcoholism, or in
untreated (or inadequately treated) type 1 diabetes mellitus. Ketone bodies are readily
transported into tissues outside the liver and converted into acetyl-CoA, which then enters the
citric acid cycle and is oxidized in the mitochondria for energy. In the brain, ketone bodies are
also used to make acetyl-CoA into long-chain fatty acids.

Ketone bodies are produced by the liver under the circumstances listed above, resultant of
intense gluconeogenesis, which is the production of glucose from non-carbohydrate sources
(including fatty acids). They are therefore always released into the blood by the liver together
with newly produced glucose after the liver glycogen stores have been depleted (these
glycogen stores are depleted within the first 24 hours of fasting).

When two acetyl-CoA molecules lose their -CoAs (or coenzyme A groups), they can form a
(covalent) dimer called acetoacetate. β-hydroxybutyrate is a reduced form of acetoacetate, in
which the ketone group is converted into an alcohol (or hydroxyl) group (see illustration on the
right). Both are 4-carbon molecules that can readily be converted back into acetyl-CoA by most
tissues of the body, with the notable exception of the liver. Acetone is the decarboxylated
form of acetoacetate which cannot be converted back into acetyl-CoA except via detoxification
in the liver where it is converted into lactic acid, which can, in turn, be oxidized into pyruvic
acid, and only then into acetyl-CoA.

Ketone bodies have a characteristic smell, which can easily be detected in the breath of
persons in ketosis and ketoacidosis. It is often described as fruity or like nail polish remover
(which usually contains acetone or ethyl acetate).

Production

Fats stored in adipose tissue are released from the fat cells into the blood as free fatty acids
and glycerol when insulin levels are low and glucagon and epinephrine levels in the blood are
high. This occurs between meals, during fasting, starvation and strenuous exercise, when
blood glucose levels are likely to fall. Fatty acids are very high energy fuels and are taken up by
all metabolizing cells that have mitochondria. This is because fatty acids can only be
metabolized in the mitochondria. Red blood cells do not contain mitochondria and are
therefore entirely dependent on anaerobic glycolysis for their energy requirements. In all
other tissues, the fatty acids that enter the metabolizing cells are combined with coenzyme A
to form acyl-CoA chains. These are transferred into the mitochondria of the cells, where they
are broken down into acetyl-CoA units by a sequence of reactions known as β-oxidation.

The acetyl-CoA produced by β-oxidation enters the citric acid cycle in the mitochondrion by
combining with oxaloacetate to form citrate. This results in the complete combustion of the
acetyl group of acetyl-CoA to CO2 and water. The energy released in this process is captured in
the form of 1 GTP and 11 ATP molecules per acetyl group (or acetic acid molecule) oxidized.
This is the fate of acetyl-CoA wherever β-oxidation of fatty acids occurs, except under certain
circumstances in the liver. In the liver oxaloacetate is wholly or partially diverted into the
gluconeogenic pathway during fasting, starvation, a low carbohydrate diet, prolonged
strenuous exercise, and in uncontrolled type 1 diabetes mellitus. Under these circumstances
oxaloacetate is hydrogenated to malate which is then removed from the mitochondrion to be
converted into glucose in the cytoplasm of the liver cells, from where the glucose is released
into the blood.In the liver, therefore, oxaloacetate is unavailable for condensation with acetyl-
CoA when significant gluconeogenesis has been stimulated by low (or absent) insulin and high
glucagon concentrations in the blood. Under these circumstances, acetyl-CoA is diverted to the
formation of acetoacetate and beta-hydroxybutyrate.[1] Acetoacetate, beta-hydroxybutyrate,
and their spontaneous breakdown product, acetone,[5] are known as ketone bodies. The
ketone bodies are released by the liver into the blood. All cells with mitochondria can take
ketone bodies up from the blood and reconvert them into acetyl-CoA, which can then be used
as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the
gluconeogenic pathway in the way that the liver does this. Unlike free fatty acids, ketone
bodies can cross the blood-brain barrier and are therefore available as fuel for the cells of the
central nervous system, acting as a substitute for glucose, on which these cells normally
survive.The occurrence of high levels of ketone bodies in the blood during starvation, a low
carbohydrate diet and prolonged heavy exercise can lead to ketosis, and in its extreme form in
out-of-control type 1 diabetes mellitus, as ketoacidosis.

Acetoacetate has a highly characteristic smell, for the people who can detect this smell, which
occurs in the breath and urine during ketosis. On the other hand, most people can smell
acetone, whose "sweet & fruity" odor also characterizes the breath of persons in ketosis or,
especially, ketoacidosis.

Ketone bodies as source of fuel

Ketone bodies can be utilized as fuel in the heart, brain and muscle, but not the liver. They
yield 2 guanosine triphosphate (GTP) and 22 adenosine triphosphate (ATP) molecules per
acetoacetate molecule when oxidized in the mitochondria. Ketone bodies are transported
from the liver to other tissues, where acetoacetate and β-hydroxybutyrate can be reconverted
to acetyl-CoA to produce reducing equivalents (NADH and FADH2), via the citric acid cycle.
Though it is the source of ketone bodies, the liver cannot use them for energy because it lacks
the enzyme thiophorase (β-ketoacyl-CoA transferase). Acetone is taken up by the liver in low
concentrations and undergoes detoxification through the methylglyoxal pathway which ends
with lactate. Acetone in high concentrations, as can occur with prolonged fasting or a
ketogenic diet, is absorbed by cells outside the liver and metabolized through a different
pathway via propylene glycol. Though the pathway follows a different series of steps requiring
ATP, propylene glycol can eventually be turned into pyruvate.

The brain gets a portion of its fuel requirements from ketone bodies when glucose is less
available than normal. In the event of low glucose concentration in the blood, most other
tissues have alternative fuel sources besides ketone bodies and glucose (such as fatty acids),
but current research indicates that the brain has an obligatory requirement for some glucose.
After strict fasting for 3 days, the brain gets 25% of its energy from ketone bodies. After about
24 days, ketone bodies become the major fuel of the brain, making up to two-thirds of brain
fuel consumption. Many studies suggest that human brain cells can survive with little or no
glucose, but proving the point is ethically questionable. uring the initial stages of ketosis, the
brain does not burn ketones, since they are an important substrate for lipid synthesis in the
brain. Furthermore, ketones produced from omega-3 fatty acids may reduce cognitive
deterioration in old age.

Utilization of ketone bodies as a source of energy is a sign of metabolic flexibility, which is

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