Editing Ketone bodies (section)

==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>