Editing Ketone bodies

{{Short description|Chemicals produced during fat metabolism}}
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|header=Ketone bodies
|image1=Aceton.svg
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|caption1=[[Acetone]]
|image2=3-Keto butyric acid Structural Formula V1.svg
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|caption2=[[Acetoacetic acid]]
|image3=(R)-3-Hydroxy butyric acid Structural Formula V1.svg
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|caption3=(''R'')-[[beta-Hydroxybutyric acid|''beta''-Hydroxybutyric acid]]
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'''Ketone bodies''' are [[water-soluble]] [[molecule]]s  or compounds that contain the [[ketone|ketone groups]] produced from [[fatty acids]] by the liver ([[ketogenesis]]).<ref>{{Cite journal |last1=Cahill |first1=George F. |last2=Veech |first2=Richard L. |date=2003 |title=Ketoacids? Good medicine? |journal=Transactions of the American Clinical and Climatological Association |volume=114 |pages=149–61; discussion 162–63 |issn=0065-7778 |pmc=2194504 |pmid=12813917}}</ref><ref name=stryer2>{{cite book |last1= Stryer |first1= Lubert | title=Biochemistry. | edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 510–15, 581–613, 775–78 |isbn= 0-7167-2009-4 }}</ref> Ketone bodies are readily transported into tissues outside the liver, where they are converted into [[acetyl-CoA]] (acetyl-Coenzyme A){{snd}}which then enters the [[citric acid cycle|citric acid cycle (Krebs cycle)]] and is oxidized for energy.<ref name="doi.org">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 {{Webarchive|url=https://web.archive.org/web/20240306103343/https://www.nature.com/articles/s42255-022-00528-6 |date=2024-03-06 }}</ref><ref>{{cite book | author1=Mary K. Campbell | author2=Shawn O. Farrell | year=2006 | page=[https://archive.org/details/biochemistry00camp_0/page/579 579] | title=Biochemistry | edition=5th | publisher=Cengage Learning | isbn=0-534-40521-5 | url-access=registration | url=https://archive.org/details/biochemistry00camp_0/page/579 }}</ref> These liver-derived ketone groups include [[acetoacetic acid]] (acetoacetate), [[beta-Hydroxybutyric acid|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]]), [[Low-carbohydrate diet|carbohydrate restrictive diets]], [[starvation]], prolonged intense [[exercise]],<ref>{{cite journal |last1= Koeslag |first1= J.H. |last2= Noakes |first2= T.D.|last3=Sloan | first3=A.W. |title= Post-exercise ketosis |publication-date= 1980|volume= 301| pages= 79–90| journal = Journal of Physiology | doi=10.1113/jphysiol.1980.sp013190|pmid= 6997456 |pmc= 1279383 |year= 1980 }}</ref> alcoholism, or during untreated (or inadequately treated) [[Diabetes mellitus#Type 1|type 1 diabetes mellitus]]. Ketone bodies are produced in liver cells by the breakdown of fatty acids.<ref>{{cite book |last1=Berg |first1=Jeremy |title=Biochemistry |date=2019 |publisher=MacMillan |isbn=9781319402853 |page=724 |edition=9 }}</ref> 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.)<ref name=stryer2 /> Ketone bodies are also produced in [[glial cells]] under periods of food restriction to sustain memory formation.<ref>{{cite journal |last1=Silva |first1=Bryon |last2=Mantha |first2=Olivier L. |last3=Schor |first3=Johann |last4=Pascual |first4=Alberto |last5=Plaçais |first5=Pierre-Yves |last6=Pavlowsky |first6=Alice |last7=Preat |first7=Thomas |title=Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation |journal=Nature Metabolism |date=17 February 2022 |volume=4 |issue=2 |pages=213–24 |doi=10.1038/s42255-022-00528-6|pmid=35177854 |pmc=8885408 }}</ref>

When two acetyl-CoA molecules lose their -CoAs (or [[Coenzyme A|coenzyme A groups]]), they can form a (covalent) [[dimer (chemistry)|dimer]] called acetoacetate. [[Beta-Hydroxybutyric acid|β-hydroxybutyrate]] is a [[organic redox reaction|reduced]] form of acetoacetate, in which the ketone group is converted into an [[Alcohol (chemistry)|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 [[fruit]]y or like [[nail polish remover]] (which usually contains acetone or [[ethyl acetate]]).

Apart from the three endogenous ketone bodies, other ketone bodies like [[3-Oxopentanoic acid|β-ketopentanoate]] and [[3-Hydroxypentanoic acid|β-hydroxypentanoate]] may be created as a result of the metabolism of synthetic [[triglycerides]], such as [[triheptanoin]].

==Production==
[[Image:Acetyl-CoA-2D colored.svg|thumb|300 px|[[Acetyl-CoA]] with the [[Acetyl|acetyl group]] indicated in blue.]]
Fats stored in [[adipose tissue]] are released from the [[Adipocytes|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 sugar level|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.<ref name=stryer2 /><ref name="oxidation_of_fats">{{Cite web |url=http://pharmaxchange.info/press/2013/10/oxidation-of-fatty-acids/ |title=Oxidation of fatty acids |date=11 October 2013 |access-date=2015-12-17 |archive-date=2018-01-08 |archive-url=https://web.archive.org/web/20180108172703/http://pharmaxchange.info/press/2013/10/oxidation-of-fatty-acids/ |url-status=live }}</ref> [[Erythrocytes|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 [[Beta-oxidation|β-oxidation]].<ref name=stryer2 /><ref name="oxidation_of_fats" />

The acetyl-CoA produced by β-oxidation enters the citric acid cycle in the mitochondrion by combining with [[Oxaloacetic acid|oxaloacetate]] to form [[citric acid|citrate]]. This results in the complete combustion of the acetyl group of acetyl-CoA (see diagram above, on the right) to CO<sub>2</sub> and water. The energy released in this process is captured in the form of 1 [[Guanosine triphosphate|GTP]] and 9 [[Adenosine triphosphate|ATP]] molecules per acetyl group (or [[acetic acid]] molecule) oxidized.<ref name=stryer2 /><ref name="oxidation_of_fats" /> 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 [[gluconeogenesis|gluconeogenic pathway]] during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled [[Diabetes mellitus#Type 1|type 1 diabetes mellitus]]. Under these circumstances oxaloacetate is hydrogenated to [[Malic acid|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.<ref name=stryer2 /> 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.<ref name=stryer2 /> Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone,<ref>[http://watcut.uwaterloo.ca/webnotes/Metabolism/fatKetoneBodyMetabolism.html Ketone body metabolism] {{Webarchive|url=https://web.archive.org/web/20160922094349/http://watcut.uwaterloo.ca/webnotes/Metabolism/fatKetoneBodyMetabolism.html |date=2016-09-22 }}, University of Waterloo</ref> 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.<ref name=stryer2 /> 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.<ref>{{Cite web |url=http://www.diabetes.org/living-with-diabetes/complications/ketoacidosis-dka.html |title=American Diabetes Association-Ketoacidosis |access-date=2010-03-02 |archive-date=2010-04-29 |archive-url=https://web.archive.org/web/20100429123055/http://www.diabetes.org/living-with-diabetes/complications/ketoacidosis-dka.html |url-status=dead }}</ref>

==Fuel utilization across different organs==
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 β-hydroxybutyrate can be reconverted to acetyl-CoA to produce reducing equivalents ([[NADH]] and [[FADH2|FADH<sub>2</sub>]]), 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.<ref name="Environmental Protection Agency; Toxicological Review of Acetone (CAS No. 67-64-1)">{{Cite web |url=http://www.epa.gov/iris/toxreviews/0128tr.pdf |title=Archived copy |access-date=2013-09-18 |archive-date=2015-09-24 |archive-url=https://web.archive.org/web/20150924074331/http://www.epa.gov/iris/toxreviews/0128tr.pdf |url-status=dead }}</ref>

=== Heart ===
The heart preferentially uses fatty acids as fuel under normal physiologic conditions. However, under [[Ketosis|ketotic]] conditions, the heart can effectively use ketone bodies for this purpose.<ref>{{cite journal |vauthors=Kodde IF, van der Stok J, Smolenski RT, de Jong JW |title=Metabolic and genetic regulation of cardiac energy substrate preference |journal=Comp. Biochem. Physiol. A|volume=146 |issue=1 |pages=26–39 |date=January 2007 |pmid=17081788 |doi=10.1016/j.cbpa.2006.09.014 }}</ref>

=== 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 [[Glia|glial cells]] can fuel neurons with locally synthesized ketone bodies to sustain memory formation upon food restriction.<ref name="doi.org"/>

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.<ref>{{cite book|last1=Clarke|first1=DD|last2=Sokoloff|first2=L|editor1-last=Siegel|editor1-first=GJ|editor2-last=Agranoff|editor2-first=BW|editor3-last=Albers|editor3-first=RW|title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects|chapter=Substrates of Cerebral Metabolism|date=1999|publisher=Lippincott-Raven|location=Philadelphia|edition=6th|url=https://www.ncbi.nlm.nih.gov/books/NBK28048/|access-date=2017-09-02|archive-date=2019-03-23|archive-url=https://web.archive.org/web/20190323172750/https://www.ncbi.nlm.nih.gov/books/NBK28048/|url-status=live}}</ref> After strict [[fasting]] for 3 days, the brain gets 25% of its energy from ketone bodies.<ref>{{cite journal | pmid = 8263048 | year = 1994 | last1 = Hasselbalch | first1 = SG | last2 = Knudsen | first2 = GM | last3 = Jakobsen | first3 = J | last4 = Hageman | first4 = LP | last5 = Holm | first5 = S | last6 = Paulson | first6 = OB | title = Brain metabolism during short-term starvation in humans. | volume = 14 | issue = 1 | pages = 125–31 | doi = 10.1038/jcbfm.1994.17 | journal = Journal of Cerebral Blood Flow and Metabolism| doi-access = free }}</ref> After about 24 days, ketone bodies become the major fuel of the brain, making up to two-thirds of brain fuel consumption.<ref name="Cahill 2006" /> Many studies suggest that human brain cells can survive with little or no glucose, but proving the point is [[Human subject research|ethically questionable]].<ref name="Cahill 2006">Cahill GF. "Fuel metabolism in starvation". ''Annu Rev Nutr'' 2006;26:1–22</ref> During the initial stages of ketosis, the brain does not burn ketones, since they are an important substrate for [[Lipid metabolism|lipid synthesis]] in the brain. Furthermore, ketones produced from [[omega-3 fatty acid]]s may reduce [[Aging-associated diseases|cognitive deterioration]] in [[old age]].<ref>{{Cite journal | last1 = Freemantle | first1 = E. | last2 = Vandal | first2 = M. N. | last3 = Tremblay-Mercier | first3 = J. | last4 = Tremblay | first4 = S. B. | last5 = Blachère | first5 = J. C. | last6 = Bégin | first6 = M. E. | last7 = Thomas Brenna | first7 = J. | last8 = Windust | first8 = A. | last9 = Cunnane | first9 = S. C. | doi = 10.1016/j.plefa.2006.05.011 | title = Omega-3 fatty acids, energy substrates, and brain function during aging | journal = Prostaglandins, Leukotrienes and Essential Fatty Acids | volume = 75 | issue = 3 | pages = 213–20 | year = 2006 | pmid =  16829066}}</ref>

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 [[HMGCS2]] (and consequently this ability) in three large-brained mammalian lineages ([[cetacean]]s, [[elephant]]s&ndash;[[mastodon]]s, [[Megachiroptera|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.<ref>{{cite journal |last1=Jebb |first1=David |last2=Hiller |first2=Michael |title=Recurrent loss of HMGCS2 shows that ketogenesis is not essential for the evolution of large mammalian brains |journal=eLife |date=16 October 2018 |volume=7 |pages=e38906 |doi=10.7554/eLife.38906|pmid=30322448 |pmc=6191284 |doi-access=free }}</ref>

==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 {{nowrap|1 mg/dL}}. Their excretion in urine is very low and undetectable by routine urine tests (Rothera's test).<ref>{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK247/|title=Clinical Methods: The History, Physical, and Laboratory Examinations|last1=Comstock|first1=John P.|last2=Garber|first2=Alan J.|date=1990|publisher=Butterworths|isbn=040990077X|editor-last=Walker|editor-first=H. Kenneth|edition=3rd|location=Boston|pmid=21250091|editor-last2=Hall|editor-first2=W. Dallas|editor-last3=Hurst|editor-first3=J. Willis|access-date=2017-12-19|archive-date=2017-09-10|archive-url=https://web.archive.org/web/20170910175430/https://www.ncbi.nlm.nih.gov/books/NBK247/|url-status=live}}</ref>

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 [[diabetic ketoacidosis]]. Under these circumstances, the low or absent insulin levels in the blood, combined with the inappropriately high glucagon concentrations,<ref>{{cite journal |last1=Koeslag |first1=J.H. |last2=Saunders |first2=P.T. |last3=Terblanche |first3=E.|title= Topical Review: A reappraisal of blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus/syndrome X complex |journal=Journal of Physiology |volume=549 |issue=Pt 2 |pages=333–46 |doi=10.1113/jphysiol.2002.037895 |pmid=12717005 |pmc=2342944|year=2003 }}</ref> induce the liver to produce glucose at an inappropriately increased rate, causing acetyl-CoA resulting from the beta-oxidation of fatty acids, to be converted into ketone bodies. The resulting very high levels of ketone bodies lower the pH of the blood plasma, which reflexively triggers the kidneys to excrete urine with very high acid levels. The high levels of glucose and ketones in the blood also spill passively into the urine (due to the inability of the renal tubules to reabsorb glucose and ketones from the tubular fluid, being overwhelmed by the high volumes of these substances being filtered into the tubular fluid). The resulting [[osmotic diuresis]] of glucose causes the removal of water and [[electrolyte]]s 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 {{nowrap|0.5–5 mM}} whereas the pathological ketoacidosis is {{nowrap|15–25 mM}}.{{Citation needed|date=March 2022}}

The process of ketosis has been studied for its effects in improving the cognitive symptoms of [[neurodegenerative disease]]s including [[Alzheimer's disease]].<ref name="Jensen">{{cite journal |last1=Jensen |first1=NJ |last2=Wodschow |first2=HZ |last3=Nilsson |first3=M |last4=Rungby |first4=J |title=Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases |journal=International Journal of Molecular Sciences |date=20 November 2020 |volume=21 |issue=22 |page=8767 |doi=10.3390/ijms21228767 |doi-access=free |pmid=33233502|pmc=7699472 }}</ref> Clinical trials have also looked to ketosis in children for [[Angelman syndrome]].<ref>{{Cite web|url = https://clinicaltrials.gov/ct2/show/NCT03644693|title = Evaluation of the Safety and Tolerability of a Nutritional Formulation in Angelman Syndrome|date = 18 August 2020|access-date = 9 February 2022|archive-date = 9 February 2022|archive-url = https://web.archive.org/web/20220209094610/https://clinicaltrials.gov/ct2/show/NCT03644693|url-status = live}}</ref>

== See also ==
* [[Fatty acid metabolism]]

== References ==
{{reflist}}

==External links==
* {{eMedicine|emerg|135}} – Diabetic Ketoacidosis
* [https://web.archive.org/web/20190518163241/http://www.unisanet.unisa.edu.au/08366/h%26p2fat.htm Fat metabolism at unisanet.unisa.edu.au]
* {{MeshName|Ketone+Bodies}}
* {{cite journal | pmc = 2564331| year = 2006| last1 = McGuire| first1 = L. C| title = Alcoholic ketoacidosis| journal = Emergency Medicine Journal| volume = 23| issue = 6| pages = 417–20| last2 = Cruickshank| first2 = A. M| last3 = Munro| first3 = P. T| doi = 10.1136/emj.2004.017590| pmid = 16714496}}

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