Ketogenese

Ketogenesis, or Ketogenese, is the hepatic production of ketone bodies during periods of limited carbohydrate availability. The process occurs mainly in liver mitochondria and generates acetone, acetoacetate, and beta-hydroxybutyrate from acetyl-CoA derived primarily from fatty acid beta-oxidation. Ketone bodies provide an important alternative energy source for peripheral tissues when glucose is scarce. The liver exports the ketone bodies to the bloodstream, but it cannot use them itself because it lacks the enzyme succinyl-CoA:3-ketoacid CoA transferase (SCOT).

Biochemical steps begin with the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA via thiolase. Acetoacetyl-CoA then combines with another acetyl-CoA through HMG-CoA synthase to produce HMG-CoA, which is cleaved by HMG-CoA lyase to yield acetoacetate. Acetoacetate can be reduced to beta-hydroxybutyrate depending on the cellular NADH/NAD+ ratio, and it can also spontaneously decarboxylate to acetone. In extrahepatic tissues, ketone bodies are converted back to acetyl-CoA for entry into the TCA cycle, a process that requires SCOT and a supply of succinyl-CoA.

Regulation and physiological role: Ketogenesis is promoted by low insulin and high glucagon or catecholamine levels, which stimulate lipolysis and fatty acid supply. It is especially prominent during prolonged fasting, uncontrolled diabetes, or adherence to very-low-carbohydrate ketogenic diets. Physiological ketosis can spare glucose for the brain and other organs, but excessive ketone production in diabetes can lead to ketoacidosis, a dangerous condition. Ketone production and utilization reflect a balance between substrate supply and enzymatic capacity in the liver and peripheral tissues.