Ketogenesis

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

Ketogenesis is the

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]

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

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

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

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]

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

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

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

References

  1. ^
    ISBN 9780123877840. Figure 8.57: Metabolism of L-leucine
    .
  2. ^
    ISBN 9780123877840
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  7. OCLC 938920491.{{cite book}}: CS1 maint: multiple names: authors list (link
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  10. ^ "Ketogensis in Low Glucose Levels". Archived from the original on 2021-10-23. Retrieved 2018-11-22.
  11. ^
    OCLC 828664654.{{cite book}}: CS1 maint: multiple names: authors list (link
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  12. ^
    PMID 10634967
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  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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  15. PMID 4553872
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  16. PMID 6157353
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  17. ^ "Ketogenesis". snst-hu.lzu.edu.cn. Archived from the original on 2020-02-04. Retrieved 2020-02-04.
  18. PMID 32144120
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  19. PMID 26011473
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External links
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