Ketogenesis

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

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Production

Ketone bodies are produced mainly in the mitochondria of liver cells. Its synthesis occurs in response to low carbohydrate 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 also known as lipids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA. Normally, 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; if not oxidized to form usable energy, it is the source of the two other ketone bodies below.
• Acetone; is not used as an energy source, but is instead exhaled or excreted as waste.
• β-hydroxybutyrate; it is not technically a ketone according to IUPAC nomenclature.

Each of these compounds are 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 or not.

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. This is very rare, and, in general, happens only in untreated Type I diabetes (see diabetic ketoacidosis) and in alcoholics after binge drinking and subsequent starvation (see alcoholic ketoacidosis).

See also

• ketone bodies
• fatty acid metabolism
• Ketosis