Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl-Coenzyme A) – which then enters the citric acid cycle (Krebs cycle) and is oxidized for energy. These liver-derived ketone groups include acetoacetic acid (acetoacetate), beta-hydroxybutyrate, and acetone, a spontaneous breakdown product of acetoacetate (see graphic). Ketone bodies are produced by the liver during periods of caloric restriction of various scenarios: low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise, alcoholism, or during untreated (or inadequately treated) type 1 diabetes mellitus. Ketone bodies are produced in liver cells by the breakdown of fatty acids. They are released into the blood after glycogen stores in the liver have been depleted. (Glycogen stores typically 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). Apart from the three endogenous ketone bodies, other ketone bodies like β-ketopentanoate and β-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides, such as triheptanoin.
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 (see diagram above, on the right) to CO2 and water. The energy released in this process is captured in the form of 1 GTP and 9 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. Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone, 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.
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