Ketone bodies are three water-soluble molecules that are produced by the liver from fatty
acids during periods of low food intake or carbohydrate restriction for cells of the
body to use as energy instead of glucose.
Two of the three are used as a source of energy in the heart and brain while the third is
a degradation breakdown product of acetoacetic acid.
Radioactive tracing of acetone determines that between 2% and 30% is excreted from the
body.
Ketone bodies are picked up by cells and converted back 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
because long chain fatty acids cannot pass through the blood-brain barrier.
The liver also additionally produces glucose from non-carbohydrate sources except fatty
acids by a process called gluconeogenesis during starvation.
In the brain, ketone bodies are a vital source of energy during fasting or strenuous exercise.
Although termed "bodies", they are molecules, not particles.
The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric
acid.
Other ketone bodies such as beta-ketopentanoate and beta-hydroxypentanoate may be created
as a result of the metabolism of synthetic triglycerides such as triheptanoin.
Uses in the heart, brain and liver Ketone bodies can be used for energy.
Ketone bodies are transported from the liver to other tissues, while acetoacetate and beta-hydroxybutyrate
can be reconverted to acetyl-CoA to produce energy, via the citric acid cycle.
Ketone bodies cannot be used by the liver for energy, because the liver lacks the enzyme
�β-ketoacyl-CoA transferase, also called thiophorase.
Acetone in low concentrations is taken up by the liver and undergoes detoxification
through the methylglyoxal pathway which ends with lactate.
Acetone in high concentrations due to prolonged fasting or a ketogenic diet is absorbed by
cells other than those in the liver and enters a different pathway via 1,2-propanediol.
Though the pathway follows a different series of steps requiring ATP, can be turned into
pyruvate.
The heart preferentially utilizes fatty acids for energy under normal physiologic conditions.
However, under ketotic conditions, the heart can effectively utilize ketone bodies for
energy.
The brain gets a portion of its energy from ketone bodies when glucose is less available.
In the event of low blood glucose, most other tissues have additional energy sources besides
ketone bodies, but the brain has an obligatory requirement for some glucose.
After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of
its energy from ketone bodies.
After about 4 days, this goes up to 70%.
Furthermore, ketones produced from omega-3 fatty acids may reduce cognitive deterioration
in old age.
Production
Ketone bodies are produced from acetyl-CoA mainly in the mitochondrial matrix of hepatocytes
when carbohydrates are so scarce that energy must be obtained from breaking down fatty
acids.
Because of the high level of acetyl CoA present in the cell, the pyruvate dehydrogenase complex
is inhibited, whereas pyruvate carboxylase becomes activated.
High levels of ATP and NADH inhibit the enzyme isocitrate dehydrogenase in the TCA cycle
and as a result cause an increase in the concentration of malate.
The malate then leaves the mitochondrion and undergoes gluconeogenesis.
The elevated level of NADH and ATP result from β-oxidation of fatty acids.
Unable to be used in the citric acid cycle, the excess acetyl-CoA is therefore rerouted
to ketogenesis.
Such a state in humans is referred to as the fasted state.
Acetone is produced by spontaneous decarboxylation of acetoacetate, meaning this ketone body
will break down in five hours if it is not used for energy and be removed as waste, or
converted to Pyruvate.
This "use it or lose it" factor may contribute to the weight loss found in ketogenic diets.
Acetone cannot be converted back to acetyl-CoA, so it is excreted in the urine, or exhaled
unless first converted to Pyruvate.
Acetone is responsible for the characteristic "Sweet & fruity" odor of the breath of persons
in ketoacidosis.
Ketosis and ketoacidosis In normal individuals, there is a constant
production of ketone bodies by the liver and their utilization by extrahepatic tissues.
The concentration of ketone bodies in blood is maintained around 1 mg/dl.
Their excretion in urine is very low and undetectable by routine urine tests.
When the rate of synthesis of ketone bodies exceeds the rate of utilization, their concentration
in blood increases; this is known as ketonemia.
This is followed by ketonuria – excretion of ketone bodies in urine.
The overall picture of ketonemia and ketonuria is commonly referred as ketosis.
Smell of acetone in breath is a common feature in ketosis.
When a type 1 diabetic suffers a biological stress event or fails to administer enough
insulin they may suffer the pathological condition ketoacidosis.
Liver cells increase metabolism of fatty acids into ketones in an attempt to supply energy
to peripheral cells which are unable to transport glucose in the absence of insulin.
The resulting very high levels of blood glucose and ketone bodies lower the pH of the blood
and trigger the kidneys to attempt to excrete the glucose and ketones.
Osmotic diuresis of glucose will cause further removal of water and electrolytes from the
blood resulting in potentially fatal dehydration, tachycardia and hypotension.
Individuals who follow a low-carbohydrate diet will also develop ketosis, sometimes
called nutritional ketosis, but the level of ketone body concentrations are on the order
of 0.5-5 mM whereas the pathological ketoacidosis is 15-25 mM.
As the mainstream diet of diabetic patients is so high in carbohydrate, ketosis is rarely
seen without ketoacidosis resulting from low serum insulin levels.
Many medical practitioners mistake well regulated nutritional ketosis for pathological ketoacidosis.
Impact upon pH Both acetoacetic acid and beta-hydroxybutyric
acid are acidic, and, if levels of these ketone bodies are too high, the pH of the blood drops,
resulting in ketoacidosis, a complication of untreated Type I diabetes, and sometimes
in end stage Type II.
See also Fatty acid metabolism
Ketogenesis Ketogenic diet
Ketones Ketosis
References
External links emerg/135 at eMedicine - Diabetic Ketoacidosis
Fat metabolism at unisanet.unisa.edu.au NHS Direct Online Health Encyclopaedia, Ketosis
BioCarta Pathways Formation of Ketone Bodies Ketone Bodies at the US National Library of
Medicine Medical Subject Headings