Ketone bodies

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

Ketone bodies are three water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone) that are produced by the liver from fatty acids[1] during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise,[2] or in untreated (or inadequately treated) type 1 diabetes mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy.[3] In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids. The latter cannot be obtained from the blood, because they cannot pass through the blood–brain barrier.

Ketone bodies are produced by the liver under the circumstances listed above (i.e. fasting, starving, low carbohydrate diets, prolonged exercise and untreated type 1 diabetes mellitus) as a result of intense gluconeogenesis, which is the production of glucose from non-carbohydrate sources (not including fatty acids).[1] They are therefore always released into the blood by the liver together with newly produced glucose, after the liver glycogen stores have been depleted. (These glycogen stores are depleted after only 24 hours of fasting.)[1]

When two acetyl-CoA molecules lose their -CoAs, (or Co-enzyme A groups) they can form a (covalent) dimer called acetoacetate. Beta-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, acetone, acetoacetic acid, and beta-hydroxybutyric acid,[4] other ketone bodies like beta-ketopentanoate and beta-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides, such as triheptanoin.

Production

Acetyl-CoA with the acetyl group indicated in blue.

Fats stored in adipose tissue are released from the 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 glucose levels are likely to fall. Fatty acids are very high energy fuels, and are taken up by all metabolizing cells which have mitochondria. This is because fatty acids can only be metabolized in the mitochondria.[1][5] Red blood cells do not contain mitochondria and are therefore entirely dependent on glycolysis (the fermentation of glucose into lactic acid) for their energy requirements. In all other tissues the fatty acids that enter the metabolizing cells are combined with co-enzyme 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 β-oxidation.[1][5]

The acetyl-CoA produced by β-oxidation enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate. This results in the complete combustion of the acetyl group of acetyl-CoA (see diagram above, on the right) to CO2 and water. The energy released in this process is captured in the form of 1 GTP and 11 ATP molecules per acetyl group (or acetic acid molecule) oxidized.[1][5] 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 gluconeogenic pathway during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled 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 it is released into the blood.[1] 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.[1] Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone,[6] are frequently, but confusingly, known as ketone bodies (as they are not "bodies" at all, but water-soluble chemical substances). 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.[1] The occurrence of high levels of ketone bodies in the blood during starvation, a low carbohydrate diet, prolonged heavy exercise and uncontrolled type 1 diabetes mellitus is known as 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.[7]

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.[8]

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.[9]

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 likely has an obligatory requirement for some glucose.[10] After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of its energy from ketone bodies.[11] After about 4 days, this goes up to 70%[12] (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.[13]

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

When a type 1 diabetic suffers a biological stress event (infection, heart attack, or physical trauma), or fails to administer enough insulin they may enter the pathological state of hyperglycemic ketoacidosis. Under these circumstances, the low or absent insulin levels in the blood, combined with the inappropriately high glucagon concentrations,[14] 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 ketones bodies. The resulting very high levels of ketone bodies lower the pH of the blood plasma which reflexively triggers the kidneys to excrete a very acid urine. The high levels of glucose and ketones in the blood also spill, passively, into the urine (the ability 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 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.

The process of ketosis is currently being investigated for efficacy in ameliorating the symptoms of Alzheimer's disease.

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).

See also

References

  1. 1 2 3 4 5 6 7 8 9 Stryer, Lubert (1995). Biochemistry. (Fourth ed.). New York: W.H. Freeman and Company. pp. 510–515, 581–613, 775–778. ISBN 0 7167 2009 4.
  2. ↑ Koeslag, J.H.; Noakes, T.D.; Sloan, A.W. (1980). "Post-exercise ketosis". Journal of Physiology. 301: 79–90.
  3. ↑ Mary K. Campbell; Shawn O. Farrell (2006). Biochemistry (5th ed.). Cengage Learning. p. 579. ISBN 0-534-40521-5.
  4. ↑ 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.
  5. 1 2 3 Oxidation of fatty acids
  6. ↑ Ketone body metabolism, University of Waterloo
  7. ↑ American Diabetes Association-Ketoacidosis
  8. ↑ http://www.epa.gov/iris/toxreviews/0128tr.pdf
  9. ↑ 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.
  10. ↑ Clarke, DD; Sokoloff, L (1999). Siegel, GJ; Agranoff, BW; Albers, RW, eds. Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Philadelphia: Lippincott-Raven.
  11. ↑ 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.
  12. ↑ Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1–22
  13. ↑ 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): 213–20. doi:10.1016/j.plefa.2006.05.011. PMID 16829066.
  14. ↑ Koeslag, J.H.; Saunders, P.T.; Terblanche, E. (2003). "Topical Review: A reappraisal of blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus/syndrome X complex". Journal of Physiology. 549: 333–346. doi:10.1113/jphysiol.2002.037895.

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