Ketogenesis

Ketogenesis Pathway

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. Its synthesis occurs in response to low glucose levels in the blood, and after exhaustion of cellular carbohydrate stores, such as glycogen. 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 GTP 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).

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 are:

• Acetoacetate, which, if not oxidized to form usable energy, is the source of the two other ketone bodies below
• Acetone, which, unlike free fatty acids, can 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.
• 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.

Each of these compounds is synthesized from acetyl-CoA molecules.

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 phosporylation.
• When the body has excess carbohydrates available, some glucose is fully metabolized, and some of it is stored by using acetyl-CoA to create 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. It is unknown whether ketosis has negative long-term effects.

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

• ketone bodies
• fatty acid metabolism
• Ketosis
• Ketogenic diet

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. http://www.ajcn.org/cgi/content/full/76/1/65. 
• Richard A. Paselk. (2001) Fat Metabolism 2: Ketone Bodies at Humboldt State University Retrieved 23 May 2005.