Ketone body


Ketone bodies are three different water-soluble, biochemicals that are produced as by-products when fatty acids are broken down in the liver for energy. Two of the three are used as a source of energy in the heart and brain while the third (acetone) is a breakdown product of acetoacetic acid. Radioactive tracing of acetone determines that between 2% and 30% is excreted from the body, the remainder is diverted into one of two known metabolic pathways both of which lead to pyruvate. Pyruvate can be oxidized to acetyl-CoA or it can go through gluconeogenesis to build glucose.[1] In the brain, ketone bodies are a vital source of energy during fasting or strenuous exercise.[2] Although termed "bodies", they are molecules, not particles.

The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric acid.[3] 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, where acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce energy, via the citric acid cycle. Acetone in low concentrations is taken up by the liver and goes through the methylglyoxal pathway which ends with pyruvate. 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 the end result is still pyruvate. [4]

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.[5]

The brain gets a portion of its energy from ketone bodies when glucose is less available (e.g., during fasting, strenuous exercise, low carbohydrate, ketogenic diet and in neonates). In the event of low blood glucose, most other tissues have additional energy sources besides ketone bodies (such as fatty acids), 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.[6] After about 4 days, this goes up to 70% (during the initial stages 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.[7]

Production

Ketone bodies are produced from acetyl-CoA (see ketogenesis) 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 (tricarboxylic acid cycle or the Krebs cycle) and as a result cause an increase in the concentration of malate (due to the equilibrium between itself and oxaloacetate). The malate then leaves the mitochondrion and undergoes gluconeogenesis. The elevated level of NADH and ATP result from β-oxidation of fatty acids.[8] 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.[4] 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 (as a consequence of its high vapor pressure) exhaled unless first converted to Pyruvate. Acetone is responsible for the characteristic "Sweet & fruity" odor of the breath of persons in ketoacidosis.[9]

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 (Rothera's test).

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 (sepsis, heart attack, infection) 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.[10]

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 diabetic ketoacidosis).

See also

References

External links

  • eMedicine - Diabetic Ketoacidosis
  • Fat metabolism at unisanet.unisa.edu.au
  • NHS Direct Online Health Encyclopaedia, Ketosis
  • BioCarta Pathways Formation of Ketone Bodies
  • Medical Subject Headings (MeSH)
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