Ketone bodies

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 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 (i.e. fasting, starving, low carbohydrate diets, prolonged exercise and untreated type 1 diabetes mellitus) as a result of intense gluconeogenesis, which is the production of glucose from non-carbohydrate sources (not 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 Co-enzyme A groups) they can form a (covalent) dimer called acetoacetate. Beta-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, acetone, acetoacetic acid, and beta-hydroxybutyric acid, other ketone bodies like beta-ketopentanoate and beta-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides, such as triheptanoin. 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 co-enzyme 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 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. 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. 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 beta-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 itself 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 1,2-propanediol. Though the pathway follows a different series of steps requiring ATP, 1,2-propanediol can eventually be turned into pyruvate.