Ketogenesis

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

Ketogenesis Pathway

Ketone bodies are produced mainly in the mitochondria of liver cells when carbohydrates are so scarce that energy must be obtained from breaking down fatty acids. The body gets energy from fatty acids by breaking the carbon chain down into pieces that contain only two carbon atoms. These pieces are in the form of acetyl-CoA. Normally, acetyl-CoA is oxidized in the citric acid cycle, but if insufficient glucose is available there will be a dearth of citric acid cycle intermediates and acetyl-CoA will accumulate.

The three ketone bodies are acetoacetate, beta-hydroxybutyrate and acetone. (Beta-hydroxybutyrate is not technically a ketone according to IUPAC nomenclature, but the other two are.) Acetone is not used as a fuel source, but is instead exhaled as waste. Each of these is the product of acetyl-CoA molecules combining to make larger compounds.

Ketogenesis may or may not occur, depend on how many carbohydrates are available. This is closely related to the paths of acetyl-CoA:

When the body has sufficient carbohydrates available, glucose is completely broken down to CO₂, with acetyl-CoA as an intermediate, and the CoA is recycled in this process (the citric acid cycle and electron transfer).
When the body has excess carbohydrates available, some glucose is fully metabolized, some is broken down to acetyl-CoA, but not all the way to CO₂, since not all of that energy is needed yet. Instead, acetyl-CoA molecules are combined to create fatty acids to save for later. (CoA is also recycled here.)
When the body has no 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 have been depleted to feed the gluconeogenesis pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.

HMG-CoA (β-hydroxy-β-methylglutaryl-CoA) is an intermediate in two important metabolic pathways - synthesis of ketone bodies and synthesis of cholesterol.

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 abnormally high 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).