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

Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown.


Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis can occur in response to an unavailability of blood glucose. This is caused by low glucose levels in the blood, after exhaustion of cellular carbohydrate stores, such as glycogen. Synthesis of ketones can also occur due to excessively high levels of blood glucose that are unable to be stored as glycogen in liver and muscle. 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 TCA cycle and 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 the 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 acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). Deaminated amino acids that are ketogenic, such as leucine, also feed the TCA cycle, forming acetoacetate & ACoA and thereby produce ketones.

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. Ketogenesis occurs in the mitochondria, whereas cholesterol synthesis occurs in the cytosol, hence both the processes are independently regulated.

Types of ketone bodies[edit]

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


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:

  • When the body has ample carbohydrates available as energy source, glucose is completely oxidized to CO2; acetyl-CoA is formed as an intermediate in this process, first entering the citric acid cycle followed by complete conversion of its chemical energy to ATP in oxidative phosphorylation.
  • When the body has excess carbohydrates available, some glucose is fully metabolized, and some of it is stored in the form of glycogen or, upon citrate excess, as fatty acids. (CoA is also recycled here.)
  • When the body has no free carbohydrates available, fat must be broken down into acetyl-CoA in order to get energy. Acetyl-CoA is not being recycled through the citric acid cycle because the citric acid cycle intermediates (mainly oxaloacetate) have been depleted to feed the gluconeogenesis pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.


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). Less commonly, some patients with poorly controlled type 2 diabetes may have detectable levels of plasma ketones without significant acidosis.

See also[edit]


  1. ^ Glew, Robert H. "You Can Get There From Here: Acetone, Anionic Ketones and Even-Carbon Fatty Acids can Provide Substrates for Gluconeogenesis". Retrieved August 2013. 
  2. ^ Miller DN, Bazzano G; Bazzano (1965). "Propanediol metabolism and its relation to lactic acid metabolism". Ann NY Acad Sci 119 (3): 957–973. Bibcode:1965NYASA.119..957M. doi:10.1111/j.1749-6632.1965.tb47455.x. PMID 4285478. 
  3. ^ Ruddick JA (1972). "Toxicology, metabolism, and biochemistry of 1,2-propanediol". Toxicol App Pharmacol 21: 102–111. doi:10.1016/0041-008X(72)90032-4. 

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