Ketone body

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Ketone bodies
beta-Hydroxybutyric acid

Ketone bodies are

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 (

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]

Ketone bodies are also produced in

glial cells under periods of food restriction to sustain memory formation [7]

When two acetyl-CoA molecules lose their -CoAs (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

nail polish remover (which usually contains acetone or ethyl acetate
).

Apart from the three endogenous ketone bodies, other ketone bodies like

triglycerides, such as triheptanoin
.

Production

acetyl group
indicated in blue.

Fats stored in

β-oxidation.[2][8]

The acetyl-CoA produced by β-oxidation enters the citric acid cycle in the mitochondrion by combining with

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.[2] 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.[2] Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone,[9] 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.[2] 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.[10]

Fuel utilization across different organs

Ketone bodies can be used as fuel in the

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 (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 propylene glycol. Though the pathway follows a different series of steps requiring ATP, propylene glycol can eventually be turned into pyruvate.[11]

Heart

The heart preferentially uses fatty acids as fuel under normal physiologic conditions. However, under ketotic conditions, the heart can effectively use ketone bodies for this purpose.[12]

Brain

For several decades the liver has been considered as the main supplier of ketone bodies to fuel brain energy metabolism. However, recent evidence has demonstrated that glial cells can fuel neurons with locally synthesized ketone bodies to sustain memory formation upon food restriction.[3]

The brain gets a portion of its fuel requirements from ketone bodies when glucose is less available than normal. In the event of low glucose concentration in the blood, most other tissues have alternative fuel sources besides ketone bodies and glucose (such as fatty acids), but studies have indicated that the brain has an obligatory requirement for some glucose.[13] After strict fasting for 3 days, the brain gets 25% of its energy from ketone bodies.[14] After about 24 days, ketone bodies become the major fuel of the brain, making up to two-thirds of brain fuel consumption.[15] Many studies suggest that human brain cells can survive with little or no glucose, but proving the point is ethically questionable.[15] During the initial stages of ketosis, 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.[16]

Ketogenesis helped fuel the enlargement of the human brain during its evolution. It was previously proposed that ketogenesis is key to the evolution and viability of bigger brains in general. However, the loss of

Old World fruit bats) shows otherwise. Out of the three lineages, only fruit bats have the expected sensitivity to starvation; the other two have found alternative ways to fuel the body during starvation.[17]

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).[18]

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 to as ketosis. The smell of acetoacetate and/or acetone in breath is a common feature in ketosis.

When a type 1 diabetic suffers acute biological stress (infection, heart attack, or physical trauma) or fails to administer enough insulin, they may enter the pathological state of

osmotic diuresis of glucose causes the removal of water and electrolytes from the blood resulting in potentially fatal dehydration
.

Individuals who follow a low-carbohydrate diet will also develop ketosis. This induced ketosis is 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.[citation needed
]

The process of ketosis is currently being investigated for efficacy in ameliorating the symptoms of Alzheimer's disease[20] and Angelman syndrome[21]

See also

References

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  2. ^
    ISBN 0-7167-2009-4
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  3. ^ a b Silva, B., Mantha, O. L., Schor, J., Pascual, A., Plaçais, P. Y., Pavlowsky, A., & Preat, T. (2022). Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation. Nature Metabolism, 4(2), 213–224. https://doi.org/10.1038/s42255-022-00528-6 Archived 2024-03-06 at the Wayback Machine
  4. ISBN 0-534-40521-5
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  5. PMID 6997456
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  6. ISBN 9781319402853
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  7. PMID 35177854
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  8. ^ a b c "Oxidation of fatty acids". Archived from the original on 2018-01-08. Retrieved 2015-12-17.
  9. ^ Ketone body metabolism Archived 2016-09-22 at the Wayback Machine, University of Waterloo
  10. ^ "American Diabetes Association-Ketoacidosis". Archived from the original on 2010-04-29. Retrieved 2010-03-02.
  11. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2015-09-24. Retrieved 2013-09-18.{{cite web}}: CS1 maint: archived copy as title (link)
  12. PMID 17081788
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  13. ^ Clarke, DD; Sokoloff, L (1999). "Substrates of Cerebral Metabolism". In Siegel, GJ; Agranoff, BW; Albers, RW (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Philadelphia: Lippincott-Raven. Archived from the original on 2019-03-23. Retrieved 2017-09-02.
  14. PMID 8263048
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  15. ^ a b Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1–22
  16. PMID 16829066
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  17. PMID 30322448
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  18. PMID 21250091. Archived
    from the original on 2017-09-10. Retrieved 2017-12-19.
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  20. PMID 18625458
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  21. ^ "Evaluation of the Safety and Tolerability of a Nutritional Formulation in Angelman Syndrome". 18 August 2020. Archived from the original on 9 February 2022. Retrieved 9 February 2022.

External links

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