Ketone bodies

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.

They are always released into the blood by the liver together with newly produced glucose, after the liver glycogen stores have been depleted.

Glycogen stores are depleted after only 24 hours of fasting.

Ketone bodies have a characteristic smell, easily be detected in the breath of persons in ketosis and ketoacidosis.

Ketone odor often described as fruity or like nail polish remover

Fats stored in adipose tissue are released from the fat cells into the blood as free fatty acids and glycerol.

Free fatty acids and glycerol are released when insulin levels are low and glucagon and epinephrine levels in the blood are high.

Free fatty acids and glycerol are released between meals, during fasting, starvation and strenuous exercise, when blood glucose levels are likely to fall.

Fatty acids are very high energy fuels.

Fatty acids are taken up by all metabolizing cells which have mitochondria.

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.

Neurons of the central nervous system (CNS) are also unable to uptake fatty acids because they cannot pass the blood-brain barrier.

In all other tissues the fatty acids that enter the metabolizing cells are combined with co-enzyme A to form acyl-CoA chains.

Acyl-CoA chains are then 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.

β-oxidation produced acetyl-CoA enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate, resulting in the complete combustion of the acetyl group of acetyl-CoA to CO2 and water.

Energy released in this process is captured in the form of 1 GTP and 11 ATP molecules per acetyl group 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 diverted into the gluconeogenic pathway during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled type 1 diabetes mellitus.

During fasting 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 it 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 insulin and high glucagon concentrations in the blood.

Under these circumstances acetyl-CoA is diverted to the formation of acetoacetate and beta-hydroxybutyrate.

Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone, are frequently, referred to as ketone bodies.

Ketone bodies are water-soluble chemical substances, which

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.

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.

High levels of ketone bodies in the blood during starvation, a low carbohydrate diet and prolonged heavy exercise can lead to ketosis, and in out-of-control type 1 diabetes mellitus, as ketoacidosis.

Acetoacetate has a highly characteristic smell, which occurs in the breath and urine during ketosis.

Acetone, has a sweet and fruity odor that characterizes the breath of persons in ketosis or, especially, ketoacidosis.

Ketone bodies can be used as fuels, yielding 2 GTP and 22 ATP molecules per acetoacetate molecule when oxidized in the mitochondria.

Ketone bodies are transported from the liver to other tissues, where acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce reducing equivalents (NADH and FADH2), via the citric acid cycle.

Ketone bodies cannot be used as fuel by the liver.

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.

The heart preferentially utilizes fatty acids as fuel under normal physiologic conditions.

Under ketotic conditions, the heart can effectively utilize ketone bodies for this purpose.

The brain gets a portion of its fuel requirements from ketone bodies when glucose is less available than normal.

Most tissues have alternative fuel sources besides ketone bodies and glucose, but the brain has an obligatory requirement for some glucose.

After a diet has been changed to lower blood glucose utilization for 3 days, the brain gets 25% of its energy from ketone bodies.

After about 4 days, this goes up to 70%.

Normally, 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 undetectable by routine urine tests.

When ketone body synthesis exceeds the rate of utilization, their concentration in blood increases.

Elevation of ketone bodies in blood is known as ketonemia.

Ketonemia is followed by ketonuria.

Ketonemia and ketonuria is referred to as ketosis., and the smell of acetoacetate and/or acetone in breath is a common feature in ketosis.

When a type 1 diabetic fails to administer enough insulin for their condition they may enter hyperglycemic ketoacidosis.

With hyperglycemic ketoacidosis the insufficient insulin levels in the blood, combined with the inappropriately high glucagon concentrations, induce the liver to increase glucose production, causing acetyl-CoA resulting from the beta-oxidation of fatty acids, to be converted into ketone bodies.

High levels of ketone bodies lower the pH of the blood which triggers the kidneys to excrete a very acid urine.

Individuals who follow a low-carbohydrate diet will develop ketosis,

sometimes called nutritional ketosis.

The level of ketone body concentrations in nutritional ketosis are on the order of 0.5-5 mM whereas the pathological ketoacidosis is 15-25 mM.

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.