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Ketone bodies are produced by the liver and used peripherally as an energy source when glucose is not readily available. The two main ketone bodies are acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB), while acetone is the third, and least abundant, ketone body. Ketones are always present in the blood and their levels increase during fasting and prolonged exercise. They are also found in the blood of neonates and pregnant women. Diabetes is the most common pathological cause of elevated blood ketones. In diabetic ketoacidosis (DKA), high levels of ketones are produced in response to low insulin levels and high levels of counterregulatory hormones. In acute DKA, the ketone body ratio (3HB:AcAc) rises from normal (1:1) to as high as 10:1. In response to insulin therapy, 3HB levels commonly decrease long before AcAc levels. The frequently employed nitroprusside test only detects AcAc in blood and urine. This test is inconvenient, does not assess the best indicator of ketone body levels (3HB), provides only a semiquantitative assessment of ketone levels and is associated with false-positive results. Recently, inexpensive quantitative tests of 3HB levels have become available for use with small blood samples (5-25 microl). These tests offer new options for monitoring and treating diabetes and other states characterized by the abnormal metabolism of ketone bodies.

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1. Both beta-hydroxy-beta-methylglutaryl-coenzyme A synthase and lyase activities are present in rat mesenteric lymphocytes: all of the synthase and almost all (80%) of the lyase were present in the mitochondrial compartment of the cell. 2. A high rate of acetoacetate formation was observed in mesenteric lymphocytes incubated in vitro for 60 min in the absence of added substrate; addition of pyruvate or glutamine increased the "endogenous" rate of acetoacetate formation by about 30%. 3. The rates of ketone body formation are similar to maximal rates observed for rat liver. 4. It is suggested that the high rate of endogenous acetoacetate production occurs from long chain fatty acids: this suggestion is consistent with the reported high "endogenous" rate of O2 consumption by lymphocytes. 5. Of the pyruvate metabolized via pyruvate dehydrogenase in lymphocytes, ca 50-70% could be accounted for as acetoacetate, acetate, 3-hydroxybutyrate and citrate: the fate of the remainder is not known. 6. There was a high rate of endogenous acetoacetate formation by isolated mitochondria from these cells. 7. The rate was doubled by addition of pyruvate or butyrate; it was trebled by addition of propionate, ADP or carbonyl cyanide trichloro-methoxyphenylhydrazone; but it was decreased by addition of antimycin A or glutamine. 8. It is suggested that the high rates of acetoacetate formation in these cells acts as a dynamic "buffer" system for the acetyl coenzyme A (CoA) concentration: that is, acetyl CoA is always available for fatty acid synthesis, cholesterologenesis, chain extension of fatty acids or acetylation of proteins (e.g. for covalent control of their activity) which will be demanded at different stages of the cell cycle. 9. This is another example of branch-point sensitivity in control in cells with the potential for rapid cell division.

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Ketogenesis is a metabolic pathway that produces ketone bodies, which provide an alternative form of energy for the body. The body is constantly producing small amounts of ketone bodies that can make 22 ATP each in normal circumstances, and it is regulated mainly by insulin. In a state of ketosis, ketone body production is increased when there are decreased carbohydrates or increased fatty acids. However, ketoacidosis can occur if too many ketone bodies accumulate, such as in cases of uncontrolled diabetes.[1][2][3]

Ketogenesis produces acetone, acetoacetate, and beta-hydroxybutyrate molecules by breaking down fatty acids. These ketones are water-soluble lipid molecules made up of two R-groups attached to a carbonyl group (C = O). Because they are water-soluble, they do not require lipoproteins for transport. Of the three, acetoacetate and beta-hydroxybutyrate are acidic, having pKa values of 3.6 and 4.7, respectively.[4][5]

In healthy humans, the body is continually making a small number of ketones to be used by the body for energy. In times of fasting, even overnight while sleeping, the level of ketone bodies in the blood increases. The normal pathways to create energy involve either stored carbohydrate or non-carbohydrate substances. When ample carbohydrate stores are available, the main pathway used is glycogenolysis. This involves the breakdown of glycogen stores in muscle and liver. Gluconeogenesis, the production of glucose from non-carbohydrate sources such as lactate, is often utilized as well, especially in situations involving exercise.

When carbohydrate stores are significantly decreased or fatty acid concentration increases, there is an upregulation of the ketogenic pathway and an increased production of ketone bodies. This can be seen in conditions such as type 1 diabetes, alcoholism, and starvation. Most organs and tissues can use ketone bodies as an alternative source of energy. The brain uses them as a major source of energy during periods where glucose is not readily available. This is because, unlike other organs in the body, the brain has an absolute minimum glucose requirement. The heart typically uses fatty acids as its source of energy but also can use ketones. Although it is the primary site that produces ketone bodies, the liver does not use ketone bodies because it lacks the necessary enzyme beta ketoacyl-CoA transferase.

Acetoacetate and beta-hydroxybutyrate are the two ketone bodies used by the body for energy. Once they reach extrahepatic tissues, beta-hydroxybutyrate is converted to acetoacetate via the enzyme beta-hydroxybutyrate dehydrogenase, and acetoacetate is converted back to acetyl-CoA via the enzyme beta-ketoacyl-CoA transferase. Acetyl-CoA goes through the citric acid cycle, and after oxidative phosphorylation, produces 22 ATP per molecule. Acetone does not convert back to acetyl-CoA, so it is either excreted through urine or exhaled.

Ketone bodies produced during ketogenesis can be measured with a urinalysis. Results range from 0 (not detected) to +4 (high amount detected). Acetone produced from ketogenesis can be directly measured in blood serum, and a normal level is below 0.6 mmol/L.

Diabetic ketoacidosis (DKA) is an example involving the overproduction of ketone bodies. It occurs when there is a lack of or resistance to insulin. This usually occurs in people with type I diabetes, although it can happen to people with advanced type II diabetes as well. In most cases of type II diabetes, enough insulin production continues to prevent excessive ketogenesis.

Once carbohydrate stores become depleted and gluconeogenesis cannot occur anymore, ketogenesis is substantially increased, and greater amounts of ketone bodies are produced. Due to the acidic nature of beta-hydroxybutyrate and acetoacetate, this causes an anion gap metabolic acidosis.

The main goal of treating DKA is to resolve metabolic acidosis, which involves giving glucose and insulin to lower blood glucose levels and downregulate the ketogenic pathway and decrease the number of ketone bodies produced.

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,[5] alcoholism, or during untreated (or inadequately treated) type 1 diabetes mellitus. Ketone bodies are produced in liver cells by the breakdown of fatty acids.[6] 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.)[2]

When two acetyl-CoA molecules lose their -CoAs (or coenzyme A groups), they can form a (covalent) dimer called acetoacetate. -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 -ketopentanoate and -hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides, such as triheptanoin.

Ketone bodies can be used 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 -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 cannot use them for energy because it lacks the enzyme thiophorase (-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 propylene glycol. Though the pathway follows a different series of steps requiring ATP, propylene glycol can eventually be turned into pyruvate.[11] be457b7860