Ketogenesis

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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.

Production

Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis can occur in response to unavailability of blood glucose. This is caused by low glucose levels in the blood, after exhaustion of cellular carbohydrate stores, such as glycogen or, synthesis of ketones can 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 and its energy transferred as electrons to NADH, FADH₂, and ATP in the citric acid cycle (TCA cycle). However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle or 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.

Types of ketone bodies

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

Acetoacetate, which, if not oxidized to form usable energy, is the source of the two other ketone bodies below
Acetone, which can not be used by the brain for energy. Acetone is generated through the decarboxylation of acetoacetate which may occur spontaneously or through the enzyme acetoacetate decarboxylase. The body releases acetone by breathing it off.
β-hydroxybutyrate, which is not, in the technical sense, a ketone according to IUPAC nomenclature. It is generated through the action of the enzyme D-β-hydroxybutyrate dehydrogenase on acetoacetate.

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:

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.

Pathology

Ketone bodies are created at moderate levels in everyone's bodies, such as during sleep and other times when no carbohydrates are available. However, when ketogenesis is happening at higher-than-normal levels, the body is said to be in a state of ketosis.

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.

External links

Fat metabolism at University of South Australia
James Baggott. (1998) Synthesis and Utilization of Ketone Bodies at University of Utah Retrieved 23 May 2005.
Musa-Veloso K, Likhodii SS, Cunnane SC (1 July 2002). "Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic meals". Am. J. Clin. Nutr. 76 (1): 65–70. PMID 12081817.
Richard A. Paselk. (2001) Fat Metabolism 2: Ketone Bodies at Humboldt State University Retrieved 23 May 2005.

Metabolism: lipid metabolism / fatty acid metabolism, triglyceride and fatty acid enzymes

Synthesis

Malonyl-CoA synthesis	ATP citrate lyase Acetyl-CoA carboxylase

Fatty acid synthesis/ Fatty acid synthase	Beta-ketoacyl-ACP synthase Β-Ketoacyl ACP reductase 3-Hydroxyacyl ACP dehydrase Enoyl ACP reductase

Fatty acid desaturases	Stearoyl-CoA desaturase-1

Triacyl glycerol	Glycerol-3-phosphate dehydrogenase Thiokinase

Degradation

Acyl transport

Beta oxidation

General	Acyl CoA dehydrogenase (ACADL ACADM ACADS ACADVL ACADSB) Enoyl-CoA hydratase MTP: HADH HADHA HADHB Acetyl-CoA C-acyltransferase

Unsaturated	Enoyl CoA isomerase 2,4 Dienoyl-CoA reductase

Odd chain	Propionyl-CoA carboxylase

Other	Hydroxyacyl-Coenzyme A dehydrogenase

To acetyl-CoA

Malonyl-CoA decarboxylase

Aldehydes

Long-chain-aldehyde dehydrogenase

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

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