Ketogenesis

Ketogenesis is the metabolic pathway that produces ketone bodies from acetyl-CoA. In humans, it occurs primarily in the mitochondria of liver cells. The principal ketone bodies released into the circulation are acetoacetate and beta-hydroxybutyrate, while acetone is formed in smaller amounts from acetoacetate .^1,2

Ketogenesis increases when fatty-acid oxidation supplies the liver with large amounts of acetyl-CoA and relatively less of that acetyl-CoA is oxidized through the citric acid cycle. This commonly occurs during fasting and other states of reduced carbohydrate availability. Acetyl-CoA is first converted to acetoacetyl-CoA and then to hydroxymethylglutaryl-CoA (HMG-CoA). HMG-CoA is subsequently converted to acetoacetate, which can be reduced to beta-hydroxybutyrate or give rise to acetone .^1,2

Acetoacetate and beta-hydroxybutyrate are water-soluble and can leave the liver through the bloodstream. Extrahepatic tissues can convert them back into acetyl-CoA and oxidize it to produce ATP. Their contribution as fuels becomes especially important during prolonged fasting, when circulating ketone concentrations rise and tissues including the brain increasingly use them for energy .¹

Ketogenesis is distinct from ketolysis. Ketogenesis produces ketone bodies, whereas ketolysis uses them as metabolic fuel. The liver is the major ketogenic organ but cannot use the ketone bodies it produces through the usual ketolytic pathway because hepatocytes lack succinyl-CoA:3-oxoacid CoA transferase (SCOT), an enzyme required for ketolysis .^1,2