Ketogenesis

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Ketogenesis pathway. The three ketone bodies (acetoacetate, acetone, and beta-hydroxy-butyrate) are marked within orange boxes Ketogenesis.svg
Ketogenesis pathway. The three ketone bodies (acetoacetate, acetone, and beta-hydroxy-butyrate) are marked within orange boxes

Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. [1] [2] The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, [3] or others. (In rare metabolic diseases, insufficient gluconeogenesis can cause excessive ketogenesis and hypoglycemia, which may lead to the life-threatening condition known as non-diabetic ketoacidosis.) [4]

Contents

Ketone bodies are not obligately produced from fatty acids; rather a meaningful amount of them is synthesized only in a situation of carbohydrate and protein insufficiency, where only fatty acids are readily available as fuel for their production.[ citation needed ]

Recent evidence suggests that glial cells are ketogenic, supplying neurons with locally synthesized ketone bodies to sustain cognitive processes. [5]

Production

Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis can occur in response to an unavailability of blood glucose, such as during fasting. [4] Other cells, e.g. human astrocytes, are capable of carrying out ketogenesis, but they are not as effective at doing so. [6] Ketogenesis occurs constantly in a healthy individual. [7] Ketogenesis in healthy individuals is ultimately under the control of the master regulatory protein AMPK, which is activated during times of metabolic stress, such as carbohydrate insufficiency. Its activation in the liver inhibits lipogenesis, promotes fatty acid oxidation, switches off acetyl-CoA carboxylase, turns on malonyl-CoA decarboxylase, and consequently induces ketogenesis. [8] Ethanol is a potent AMPK inhibitor [9] and therefore can cause significant disruptions in the metabolic state of the liver, including halting of ketogenesis, [6] even in the context of hypoglycemia.

Ketogenesis takes place in the setting of low glucose levels in the blood, after exhaustion of other cellular carbohydrate stores, such as glycogen. [10] It can also take place when there is insufficient insulin (e.g. in type 1 (and less commonly type 2) diabetes), particularly during periods of "ketogenic stress" such as intercurrent illness. [4]

The production of ketone bodies is then initiated to make available energy that is stored as fatty acids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA. Under normal conditions, acetyl-CoA is further oxidized by the citric acid cycle (TCA/Krebs cycle) and then by the mitochondrial electron transport chain to release energy. However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle; i.e. if activity in TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacetyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). Furthermore, since there is only a limited amount of coenzyme A in the liver, the production of ketogenesis allows some of the coenzyme to be freed to continue fatty-acid β-oxidation. [11] Depletion of glucose and oxaloacetate can be triggered by fasting, vigorous exercise, high-fat diets or other medical conditions, all of which enhance ketone production. [12] Deaminated amino acids that are ketogenic, such as leucine, also feed TCA cycle, forming acetoacetate & ACoA and thereby produce ketones. [1] Besides its role in the synthesis of ketone bodies, HMG-CoA is also an intermediate in the synthesis of cholesterol, but the steps are compartmentalised. [1] [2] Ketogenesis occurs in the mitochondria, whereas cholesterol synthesis occurs in the cytosol, hence both processes are independently regulated. [2]

Ketone bodies

The three ketone bodies, each synthesized from acetyl-CoA molecules, are:

β-Hydroxybutyrate and acetoacetate can pass through membranes easily, and are therefore a source of energy for the brain, which cannot directly metabolize fatty acids. The brain receives 60-70% of its required energy from ketone bodies when blood glucose levels are low. These bodies are transported into the brain by monocarboxylate transporters 1 and 2. Therefore, ketone bodies are a way to move energy from the liver to other cells. The liver does not have the critical enzyme, succinyl CoA transferase, to process ketone bodies, and therefore cannot undergo ketolysis. [6] [11] The result is that the liver only produces ketone bodies, but does not use a significant amount of them. [16]

Regulation

Ketogenesis may or may not occur, depending on levels of available carbohydrates in the cell or body. This is closely related to the paths of acetyl-CoA: [17]

Insulin and glucagon are key regulating hormones of ketogenesis, with insulin being the primary regulator. Both hormones regulate hormone-sensitive lipase and acetyl-CoA carboxylase. Hormone-sensitive lipase produces diglycerides from triglycerides, freeing a fatty acid molecule for oxidation. Acetyl-CoA carboxylase catalyzes the production of malonyl-CoA from acetyl-CoA. Malonyl-CoA reduces the activity of carnitine palmitoyltransferase I, an enzyme that brings fatty acids into the mitochondria for β-oxidation. Insulin inhibits hormone-sensitive lipase and activates acetyl-CoA carboxylase, thereby reducing the amount of starting materials for fatty acid oxidation and inhibiting their capacity to enter the mitochondria. Glucagon activates hormone-sensitive lipase and inhibits acetyl-CoA carboxylase, thereby stimulating ketone body production, and making passage into the mitochondria for β-oxidation easier. [12] Insulin also inhibits HMG-CoA lyase, further inhibiting ketone body production. Similarly, cortisol, catecholamines, epinephrine, norepinephrine, and thyroid hormones can increase the amount of ketone bodies produced, by activating lipolysis (the mobilization of fatty acids out of fat tissue) and thereby increasing the concentration of fatty acids available for β-oxidation. [6] Unlike glucagon, catecholamines are capable of inducing lipolysis even in the presence of insulin for use by peripheral tissues during acute stress.

Peroxisome Proliferator Activated Receptor alpha (PPARα) also has the ability to upregulate ketogenesis, as it has some control over a number of genes involved in ketogenesis. For example, monocarboxylate transporter 1, [18] which is involved in transporting ketone bodies over membranes (including the blood–brain barrier), is regulated by PPARα, thus affecting ketone body transportation into the brain. Carnitine palmitoyltransferase is also upregulated by PPARα, which can affect fatty acid transportation into the mitochondria. [6]

Pathology

Both acetoacetate and beta-hydroxybutyrate are acidic, and, if levels of these ketone bodies are too high, the pH of the blood drops, resulting in ketoacidosis. Ketoacidosis is known to occur in untreated type I diabetes (see diabetic ketoacidosis) and in alcoholics after prolonged binge-drinking without intake of sufficient carbohydrates (see alcoholic ketoacidosis).[ citation needed ]

The production and use of ketones can be ineffective in people with defects in the pathway for beta-oxidation, in the genes for ketogenesis (HMGCS2 and HMGCL), for ketolysis (OXCT1, ACAT1). Defects in this pathway can cause varying degrees of inability to cope with fasting. HMGCS2 deficiency, for example, can cause hypoglycemic crises that lead to brain damage, and death. [4]

Individuals with diabetes mellitus can experience overproduction of ketone bodies due to a lack of insulin. Without insulin to help extract glucose from the blood, tissues the levels of malonyl-CoA are reduced, and it becomes easier for fatty acids to be transported into mitochondria, causing the accumulation of excess acetyl-CoA. The accumulation of acetyl-CoA in turn produces excess ketone bodies through ketogenesis. [11] The result is a rate of ketone production higher than the rate of ketone disposal, and a decrease in blood pH. [12] In extreme cases the resulting acetone can be detected in the patient's breath as a faint, sweet odor.

There are some health benefits to ketone bodies and ketogenesis as well. It has been suggested that a low-carb, high fat ketogenic diet can be used to help treat epilepsy in children. [6] Additionally, ketone bodies can be anti-inflammatory. [19] Some kinds of cancer cells are unable to use ketone bodies, as they do not have the necessary enzymes to engage in ketolysis. It has been proposed that actively engaging in behaviors that promote ketogenesis could help manage the effects of some cancers. [6]

See also

Related Research Articles

<span class="mw-page-title-main">Diabetic ketoacidosis</span> Medical condition

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 consciousness. A person's breath may develop a specific "fruity" smell. The onset of symptoms is usually rapid. People without a previous diagnosis of diabetes may develop DKA as the first obvious symptom.

<span class="mw-page-title-main">Ketone bodies</span> Chemicals produced during fat metabolism

Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA —which then enters the citric acid cycle and is oxidized for energy. These liver-derived ketone groups include acetoacetic acid (acetoacetate), beta-hydroxybutyrate, and acetone, a spontaneous breakdown product of acetoacetate.

<span class="mw-page-title-main">Acetoacetic acid</span> Chemical compound

Acetoacetic acid is the organic compound with the formula CH3COCH2COOH. 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 stable, are produced on a large scale industrially as precursors to dyes. Acetoacetic acid is a weak acid.

<span class="mw-page-title-main">Ketosis</span> Using body fats as fuel instead of carbohydrates

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 energy source for the brain in the form of ketones. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's acid–base homeostasis is maintained. This contrasts with ketoacidosis, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0 millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.

<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

Acetyl-CoA 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 to be oxidized for energy production.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is an ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the 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 medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Ketoacidosis</span> Medical condition

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 in blood pH and requires medical attention. The most common cause of ketoacidosis is diabetic ketoacidosis but can also be caused by alcohol, medications, toxins, and rarely, starvation.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

Ketotic hypoglycemia refers to any circumstance in which low blood glucose is accompanied by ketosis, the presence of ketone bodies in the blood or urine. This state can be either physiologic or pathologic; physiologic ketotic hypoglycemia is a common cause of hypoglycemia in children, often in response to stressors such as infection or fasting. Pathologic ketotic hypoglycemia is typically caused by metabolic defects, such as glycogen storage disorders.

In biochemistry and metabolism, beta oxidation (also β-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. Acetyl-CoA enters the citric acid cycle, generating NADH and FADH2, which are electron carriers used in the electron transport chain. It is named as such because the beta carbon of the fatty acid chain undergoes oxidation and is converted to a carbonyl group to start the cycle all over again. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

<span class="mw-page-title-main">Ketonuria</span> Medical condition

Ketonuria is a medical condition in which ketone bodies are present in the urine.

β-Hydroxybutyric acid Chemical compound

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-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).

Starvation response in animals is a set of adaptive biochemical and physiological changes, triggered by lack of food or extreme weight loss, in which the body seeks to conserve energy by reducing the amount of food energy it consumes.

<span class="mw-page-title-main">Glucogenic amino acid</span> Type of amino acid

A glucogenic amino acid is an amino acid that can be converted into glucose through gluconeogenesis. This is in contrast to the ketogenic amino acids, which are converted into ketone bodies.

<span class="mw-page-title-main">Ketogenic amino acid</span> Type of amino acid

A ketogenic amino acid is an amino acid that can be degraded directly into acetyl-CoA, which is the precursor of ketone bodies and myelin, particularly during early childhood, when the developing brain requires high rates of myelin synthesis. This is in contrast to the glucogenic amino acids, which are converted into glucose. Ketogenic amino acids are unable to be converted to glucose as both carbon atoms in the ketone body are ultimately degraded to carbon dioxide in the citric acid cycle.

<span class="mw-page-title-main">Acetoacetate decarboxylase</span> Enzyme

Acetoacetate decarboxylase is an enzyme involved in both the ketone body production pathway in humans and other mammals, and solventogenesis in bacteria. Acetoacetate decarboxylase plays a key role in solvent production by catalyzing the decarboxylation of acetoacetate, yielding acetone and carbon dioxide.

The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.

Exogenous ketones are a class of ketone bodies that are ingested using nutritional supplements or foods. This class of ketone bodies refers to the three water-soluble ketones. These ketone bodies are produced by interactions between macronutrient availability such as low glucose and high free fatty acids or hormone signaling such as low insulin and high glucagon/cortisol. Under physiological conditions, ketone concentrations can increase due to starvation, ketogenic diets, or prolonged exercise, leading to ketosis. However, with the introduction of exogenous ketone supplements, it is possible to provide a user with an instant supply of ketones even if the body is not within a state of ketosis before ingestion. However, drinking exogenous ketones will not trigger fat burning like a ketogenic diet.

References

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  3. ↑ Aalling, Nadia Nielsen; Nedergaard, Maiken; DiNuzzo, Mauro (July 16, 2018). "Cerebral Metabolic Changes During Sleep". Current Neurology and Neuroscience Reports. 18 (9): 57. doi:10.1007/s11910-018-0868-9. PMC   6688614 . PMID   30014344.
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  5. ↑ Silva, Bryon; Mantha, Olivier L.; Schor, Johann; Pascual, Alberto; Plaçais, Pierre-Yves; Pavlowsky, Alice; Preat, Thomas (17 February 2022). "Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation". Nature Metabolism. 4 (2): 213–224. doi:10.1038/s42255-022-00528-6. PMC   8885408 . PMID   35177854.
  6. 1 2 3 4 5 6 7 8 Grabacka M, Pierzchalska M, Dean M, Reiss K (2016). "Regulation of Ketone Body Metabolism and the Role of PPARα". International Journal of Molecular Sciences . 17 (12): E2093. doi: 10.3390/ijms17122093 . PMC   5187893 . PMID   27983603.
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  10. ↑ "Ketogensis in Low Glucose Levels". Archived from the original on 2021-10-23. Retrieved 2018-11-22.
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  12. 1 2 3 Laffel, Lori (1999-11-01). "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 . ISSN   1520-7560. PMID   10634967.
  13. ↑ Glew, Robert H. "You Can Get There From Here: Acetone, Anionic Ketones and Even-Carbon Fatty Acids can Provide Substrates for Gluconeogenesis". Archived from the original on 26 September 2013. Retrieved 8 March 2014.
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  17. ↑ "Ketogenesis". snst-hu.lzu.edu.cn. Archived from the original on 2020-02-04. Retrieved 2020-02-04.
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  19. ↑ Dupuis, Nina; Curatolo, Niccolo; Benoist, Jean-François; Auvin, Stéphane (2015). "Ketogenic diet exhibits anti-inflammatory properties". Epilepsia. 56 (7): e95–e98. doi: 10.1111/epi.13038 . ISSN   1528-1167. PMID   26011473.
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