Ketone Bodies
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Ketone bodies are
water-soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solub ...
molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
s that contain the ketone groups produced from
fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
by the liver (
ketogenesis Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under ...
). Ketone bodies are readily transported into tissues outside the liver, where they are converted into
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
(acetyl-Coenzyme A)—which then enters the citric acid cycle (Krebs cycle) and is oxidized for energy. These liver-derived ketone groups include
acetoacetic acid Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite sta ...
(acetoacetate), beta-hydroxybutyrate, and
acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...
, 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 Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
), carbohydrate restrictive diets,
starvation Starvation is a severe deficiency in caloric energy intake, below the level needed to maintain an organism's life. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, dea ...
, prolonged intense
exercise Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
, alcoholism, or during untreated (or inadequately treated)
type 1 diabetes mellitus Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
. Ketone bodies are produced in liver cells by the breakdown of fatty acids. They are released into the blood ''after''
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...
stores in the liver have been depleted. (Glycogen stores typically are depleted within the first 24 hours of fasting.) Ketone bodies are also produced in
glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
under periods of food restriction to sustain memory formation When two acetyl-CoA molecules lose their -CoAs (or coenzyme A groups), they can form a (covalent)
dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ...
called acetoacetate.
β-hydroxybutyrate β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxyb ...
is a reduced form of acetoacetate, in which the ketone group is converted into an alcohol (or
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
) 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 Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as natu ...
, 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 Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes ...
. It is often described as
fruit In botany, a fruit is the seed-bearing structure in flowering plants that is formed from the ovary after flowering. Fruits are the means by which flowering plants (also known as angiosperms) disseminate their seeds. Edible fruits in particu ...
y or like nail polish remover (which usually contains acetone or
ethyl acetate Ethyl acetate ( systematically ethyl ethanoate, commonly abbreviated EtOAc, ETAC or EA) is the organic compound with the formula , simplified to . This colorless liquid has a characteristic sweet smell (similar to pear drops) and is used in glues ...
). Apart from the three endogenous ketone bodies, other ketone bodies like β-ketopentanoate and β-hydroxypentanoate may be created as a result of the metabolism of synthetic
triglycerides A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as we ...
, such as
triheptanoin Triheptanoin, sold under the brand name Dojolvi, is a medication for the treatment of children and adults with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). The most common adverse reactions include abdominal pain, d ...
.


Production

Fats stored in
adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
are released from the
fat cells Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
into the blood as
free fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
and
glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
when
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
levels are low and
glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
and
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
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 that have
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
. This is because fatty acids can only be metabolized in the mitochondria.Oxidation of fatty acids
/ref>
Red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
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 Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
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 In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycl ...
. The acetyl-CoA produced by β-oxidation enters the citric acid cycle in the mitochondrion by combining with
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
to form
citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...
. 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 Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...
molecule) oxidized. This is the fate of acetyl-CoA wherever β-oxidation of fatty acids occurs, except under certain circumstances in the
liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
. 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 Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
. Under these circumstances oxaloacetate is hydrogenated to
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms (L ...
which is then removed from the mitochondrion to be converted into glucose in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
of the liver cells, from where the glucose is released into the blood. 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 Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
concentrations in the blood. Under these circumstances, acetyl-CoA is diverted to the formation of acetoacetate and beta-hydroxybutyrate. Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone, 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 The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
and are therefore available as fuel for the cells of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
, acting as a substitute for glucose, on which these cells normally survive. 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 Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes ...
. 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.


Fuel utilization across different organs

Ketone bodies can be used as fuel in the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
,
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
and
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
, but not the
liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
. They yield 2
guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only diffe ...
(GTP) and 22
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(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), 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 Propylene glycol (IUPAC nomenclature, IUPAC name: propane-1,2-diol) is a viscous, colorless liquid, which is nearly odorless but possesses a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH. Containing two Alcohol (chemistry), alcoho ...
. Though the pathway follows a different series of steps requiring ATP, propylene glycol can eventually be turned into pyruvate.


Heart

The heart preferentially uses fatty acids as fuel under normal physiologic conditions. However, under ketotic conditions, the heart can effectively use ketone bodies for this purpose.


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
glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
can fuel neurons with locally synthesized ketone bodies to sustain memory formation upon food restriction 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. After strict
fasting Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
for 3 days, the brain gets 25% of its energy from ketone bodies. After about 24 days, ketone bodies become the major fuel of the brain, making up to two-thirds of brain fuel consumption. Many studies suggest that human brain cells can survive with little or no glucose, but proving the point is ethically questionable.Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1–22 During the initial stages of ketosis, the brain does not burn ketones, since they are an important substrate for
lipid synthesis Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
in the brain. Furthermore, ketones produced from
omega-3 fatty acid Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...
s may reduce cognitive deterioration in
old age Old age refers to ages nearing or surpassing the life expectancy of human beings, and is thus the end of the human life cycle. Terms and euphemisms for people at this age include old people, the elderly (worldwide usage), OAPs (British usage ...
. 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 Cetacea (; , ) is an infraorder of aquatic mammals that includes whales, dolphins, and porpoises. Key characteristics are their fully aquatic lifestyle, streamlined body shape, often large size and exclusively carnivorous diet. They propel them ...
s,
elephant Elephants are the largest existing land animals. Three living species are currently recognised: the African bush elephant, the African forest elephant, and the Asian elephant. They are the only surviving members of the family Elephantidae an ...
s–
mastodon A mastodon ( 'breast' + 'tooth') is any proboscidean belonging to the extinct genus ''Mammut'' (family Mammutidae). Mastodons inhabited North and Central America during the late Miocene or late Pliocene up to their extinction at the end of th ...
s, Old World fruit bats) shows otherwise.


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 . 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 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 Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of ...
. Under these circumstances, the low or absent insulin levels in the blood, combined with the inappropriately high glucagon concentrations, 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 Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pro ...
of glucose causes the removal of water and
electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
s from the blood resulting in potentially fatal
dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
. Individuals who follow a low-carbohydrate diet will also develop ketosis. This induced ketosis is sometimes called
nutritional ketosis Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional ...
, but the level of ketone body concentrations are on the order of whereas the pathological ketoacidosis is . The process of ketosis is currently being investigated for efficacy in ameliorating the symptoms of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and
Angelman syndrome Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...


See also

* Fatty acid metabolism


References


External links

* - Diabetic Ketoacidosis
Fat metabolism at unisanet.unisa.edu.au
* * {{DEFAULTSORT:Ketone Bodies Antidepressants Histone deacetylase inhibitors Metabolism