Ketone bodies
Ketone bodies are three different water-soluble biochemicals that are produced as by-products when fatty acids are broken down for energy in the liver. Two of the three are used as a source of energy in the heart and brain while the third (acetone) is a waste product excreted from the body. In the brain, they are a vital source of energy during fasting.[1] Although termed "bodies", they are molecules, not particles.
The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric acid,[2] although beta-hydroxybutyric acid is not technically a ketone but a carboxylic acid. 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.
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Uses in the heart and brain[edit]
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.
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.[3]
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. After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of its energy from ketone bodies.[4] 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.[5]
Production[edit]
Ketone bodies are produced from acetyl-CoA (see ketogenesis) mainly in the mitochondrial matrix of hepatocytes 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 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.[6] 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, meaning this ketone body will break down in five hours if it is not needed for energy and be removed as waste. This "use it or lose it" factor contributes to much of 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. Acetone is responsible for the characteristic "Sweet & fruity" odor of the breath of persons in ketoacidosis.[7]
Ketosis and ketoacidosis[edit]
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 and glucose via glycogenolysis 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 is so high in carbohydrate that ketosis is rarely seen without starvation or ketoacidosis, many practitioners mistake well regulated nutritional ketosis for pathological ketoacidosis.[citation needed]
Impact upon pH[edit]
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 Type II (see diabetic ketoacidosis).
See also[edit]
References[edit]
- ^ 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.
- ^ 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. et al. (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.
- ^ Baynes medical biochemistry
- ^ American Diabetes Association-Ketoacidosis
External links[edit]
- 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)
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