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any of a class of organic compounds having a carbonyl group linked to a carbon atom in each of two hydrocarbon radicals

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/01/01 18:20:23」(JST)

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Chemical structures of the three ketone bodies: acetone (top), acetoacetic acid (middle), and beta-hydroxybutyric acid (bottom).

Ketone bodies are three water-soluble molecules that are produced by the liver from fatty acids during periods of low food intake (fasting) or carbohydrate restriction for cells of the body to use as energy instead of glucose. Two of the three are used as a source of energy in the heart and brain while the third (acetone) is a degradation breakdown product of acetoacetic acid. Radioactive tracing of acetone determines that between 2% and 30% is excreted from the body. Ketone bodies are picked up by cells and converted back 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, which cannot pass through the blood-brain barrier. The liver additionally produces glucose from non-carbohydrate sources other than fatty acids by a process called gluconeogenesis during starvation. In the brain, ketone bodies are a vital source of energy during fasting or strenuous exercise.^[1] Although termed "bodies", they are molecules, not particles.

The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric acid.^[2] Other ketone bodies such as beta-ketopentanoate and beta-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides such as triheptanoin.

Uses in the heart, brain and muscle (but not the liver)

Ketone bodies can be used for energy. Ketone bodies are transported from the liver to other tissues, where acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce energy, via the citric acid cycle. Ketone bodies cannot be used by the liver for energy, because the liver lacks the enzyme β-ketoacyl-CoA transferase, also called thiophorase. Acetone in low concentrations is taken up by the liver and undergoes detoxification through the methylglyoxal pathway which ends with lactate. Acetone in high concentrations due to prolonged fasting or a ketogenic diet is absorbed by cells other than those in the liver and enters a different pathway via 1,2-propanediol. Though the pathway follows a different series of steps requiring ATP, 1,2-propanediol can be turned into pyruvate.^[3]

The heart preferentially utilizes fatty acids for energy under normal physiologic conditions. However, under ketotic conditions, the heart can effectively utilize ketone bodies for energy.^[4]

The brain gets a portion of its energy from ketone bodies when glucose is less available (e.g., during fasting, strenuous exercise, low carbohydrate, ketogenic diet and in neonates). In the event of low blood glucose, most other tissues have additional energy sources besides ketone bodies (such as fatty acids), but the brain has an obligatory requirement for some glucose.^{[citation needed]} After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of its energy from ketone bodies.^[5] After about 4 days, this goes up to 70%^{[citation needed]} (during the initial stages 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.^[6]

Production

Acetyl-CoA

Ketone bodies are produced from acetyl-CoA (see ketogenesis) mainly in the mitochondrial matrix of hepatocytes (liver tissue) when carbohydrates are so scarce that energy must be obtained from breaking down fatty acids. Because of the high level of acetyl CoA present in the cell, the pyruvate dehydrogenase complex is inhibited, whereas pyruvate carboxylase becomes activated. High levels of ATP and NADH inhibit the enzyme isocitrate dehydrogenase in the TCA cycle (tricarboxylic acid cycle or the Krebs cycle) and as a result cause an increase in the concentration of malate (due to the equilibrium between itself and oxaloacetate). The malate then leaves the mitochondrion and undergoes gluconeogenesis. The elevated level of NADH and ATP result from β-oxidation of fatty acids.^[7] Unable to be used in the citric acid cycle, the excess acetyl-CoA is therefore rerouted to ketogenesis. Such a state in humans is referred to as the fasted state.

Acetone is produced by spontaneous decarboxylation of acetoacetate,^[8] meaning this ketone body will break down if it is not used for energy and be removed as waste or converted to pyruvate.^[3] This "use it or lose it" factor may contribute to the weight loss found in ketogenic diets. Acetone cannot be converted back to acetyl-CoA, so it is excreted in the urine, or (as a consequence of its high vapor pressure) exhaled unless first converted to Pyruvate. Acetone is responsible for the characteristic "Sweet & fruity" odor of the breath of persons in ketoacidosis.^[9]

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).

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 as ketosis. Smell of acetone in breath is a common feature in ketosis.

When a type 1 diabetic suffers a biological stress event (sepsis, heart attack, infection) or fails to administer enough insulin they may suffer the pathological condition ketoacidosis. Liver cells increase metabolism of fatty acids into ketones in an attempt to supply energy to peripheral cells which are unable to transport glucose in the absence of insulin. The resulting very high levels of blood glucose and ketone bodies lower the pH of the blood and trigger the kidneys to attempt to excrete the glucose and ketones. Osmotic diuresis of glucose will cause further removal of water and electrolytes from the blood resulting in potentially fatal dehydration, tachycardia and hypotension.

Individuals who follow a low-carbohydrate diet will also develop ketosis, 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.

As the mainstream diet of diabetic patients is so high in carbohydrate, ketosis is rarely seen without ketoacidosis resulting from low serum insulin levels. Many medical practitioners mistake well regulated nutritional ketosis for pathological ketoacidosis.^[10]

Impact upon pH

Both acetoacetic acid and beta-hydroxybutyric acid are acidic, and, if levels of these ketone bodies are too high, the pH of the blood drops, resulting in ketoacidosis, a complication of untreated Type I diabetes, and sometimes in end stage Type II (see diabetic ketoacidosis).

References

^ Mary K. Campbell, Shawn O. Farrell (2006). Biochemistry (5th ed.). Cengage Learning. p. 579. ISBN 0-534-40521-5.
^ Lori Laffel (1999). "Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes". Diabetes/Metabolism Research and Reviews 15 (6): 412–426. doi:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8. PMID 10634967.
^ ^a ^b http://www.epa.gov/iris/toxreviews/0128tr.pdf
^ Kodde IF, van der Stok J, Smolenski RT, de Jong JW (January 2007). "Metabolic and genetic regulation of cardiac energy substrate preference". Comp. Biochem. Physiol., Part a Mol. Integr. Physiol. 146 (1): 26–39. doi:10.1016/j.cbpa.2006.09.014. PMID 17081788.
^ Hasselbalch, SG; Knudsen, GM; Jakobsen, J; Hageman, LP; Holm, S; Paulson, OB (1994). "Brain metabolism during short-term starvation in humans.". Journal of cerebral blood flow and metabolism 14 (1): 125–31. doi:10.1038/jcbfm.1994.17. PMID 8263048.
^ Freemantle, E.; Vandal, M. N.; Tremblay-Mercier, J.; Tremblay, S. B.; Blachère, J. C.; Bégin, M. E.; Thomas Brenna, J.; Windust, A.; Cunnane, S. C. (2006). "Omega-3 fatty acids, energy substrates, and brain function during aging". Prostaglandins, Leukotrienes and Essential Fatty Acids 75 (3): 213. doi:10.1016/j.plefa.2006.05.011. edit
^ Baynes medical biochemistry
^ Ketone body metabolism, University of Waterloo
^ American Diabetes Association-Ketoacidosis
^ Thomas M. Devlin. (2010). Textbook of Biochemistry with Clinical Correlations. (7th Ed.) John Wiley & Sons. p. 699. ISBN 978-0-47-028173-4

External links

emerg/135 at eMedicine - Diabetic Ketoacidosis
Fat metabolism at unisanet.unisa.edu.au
NHS Direct Online Health Encyclopaedia, Ketosis
BioCarta Pathways Formation of Ketone Bodies
Ketone Bodies at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. 空腹時ケトアシドーシスおよびアルコール性ケトアシドーシス fasting ketosis and alcoholic ketoacidosis
2. 成人における糖尿病性ケトアシドーシスおよび高浸透圧性高血糖状態：臨床的特徴、評価、および診断 diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults clinical features evaluation and diagnosis
3. 乳児および小児における低血糖に対するアプローチ approach to hypoglycemia in infants and children
4. イソプロピルアルコール中毒 isopropyl alcohol poisoning
5. Causes of hypoglycemia in infants and children

English Journal

Ketone body metabolism and sleep homeostasis in mice.

Chikahisa S1, Shimizu N1, Shiuchi T1, Séi H2.Author information 1Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.2Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Electronic address: sei@tokushima-u.ac.jp.AbstractA link has been established between energy metabolism and sleep homeostasis. The ketone bodies acetoacetate and β-hydroxybutyrate, generated from the breakdown of fatty acids, are major metabolic fuels for the brain under conditions of low glucose availability. Ketogenesis is modulated by the activity of peroxisome proliferator-activated receptor alpha (PPARα), and treatment with a PPAR activator has been shown to induce a marked increase in plasma acetoacetate and decreased β-hydroxybutyrate in mice, accompanied by increased slow-wave activity during non-rapid eye movement (NREM) sleep. The present study investigated the role of ketone bodies in sleep regulation. Six-hour sleep deprivation increased plasma ketone bodies and their ratio (acetoacetate/β-hydroxybutyrate) in 10-week-old male mice. Moreover, sleep deprivation increased mRNA expression of ketogenic genes such as PPARα and 3-hydroxy-3-methylglutarate-CoA synthase 2 in the brain and decreased ketolytic enzymes such as succinyl-CoA: 3-oxoacid CoA transferase. In addition, central injection of acetoacetate, but not β-hydroxybutyrate, markedly increased slow-wave activity during NREM sleep and suppressed glutamate release. Central metabolism of ketone bodies, especially acetoacetate, appears to play a role in the regulation of sleep homeostasis.
Neuropharmacology.Neuropharmacology.2014 Apr;79:399-404. doi: 10.1016/j.neuropharm.2013.12.009. Epub 2013 Dec 17.
A link has been established between energy metabolism and sleep homeostasis. The ketone bodies acetoacetate and β-hydroxybutyrate, generated from the breakdown of fatty acids, are major metabolic fuels for the brain under conditions of low glucose availability. Ketogenesis is modulated by the activ
PMID 24361452

Ketone Body Therapy: From ketogenic diet to oral administration of ketone ester.

Hashim SA Md1, Vanitallie TB Md.Author information 1Columbia University College of Physicians & Surgeons.AbstractAbstract Ketone bodies (KB), acetoacetate and β-hyroxybutyrate, were considered harmful metabolic by-products when discovered in the mid-nineteenth century in urine of patients with diabetic ketoacidosis. It took physicians many years to realize KB are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KB as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer disease, there is preliminary evidence that these same areas remain capable of metabolizing KB. Because the ketogenic diet (KD) is difficult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma levels to 4-8 mM, KB esters, such as 1,3-butanediol monoester of β-hydroxybutyrate and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, Alzheimer diesease, and Parkinson disease.
Journal of lipid research.J Lipid Res.2014 Mar 5. [Epub ahead of print]
Abstract Ketone bodies (KB), acetoacetate and β-hyroxybutyrate, were considered harmful metabolic by-products when discovered in the mid-nineteenth century in urine of patients with diabetic ketoacidosis. It took physicians many years to realize KB are normal metabolites synthesized by the liver an
PMID 24598140

Cancer as a metabolic disease: implications for novel therapeutics.

Seyfried TN1, Flores RE, Poff AM, D'Agostino DP.Author information 1Biology Department, Boston College, Chestnut Hill, MA 02467, USA and.AbstractEmerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology.
Carcinogenesis.Carcinogenesis.2014 Mar;35(3):515-27. doi: 10.1093/carcin/bgt480. Epub 2013 Dec 16.
Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initia
PMID 24343361

Japanese Journal

Interaction between metabolic challenges and　productivity in high yielding dairy cows

Opsomer Geert
Japanese Journal of Veterinary Research 63(1), S1-S14, 2015-02
… Chronically elevated concentrations of non-esterified fatty acids and ketone bodies have been demonstrated to affect multiple organ systems including the immune system, the reproductive axis and the liver and are, in contrast to absolute milk yield, closely and consistently related to the final incidence of reproductive disorders. …
NAID 120005540299

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