Ketogenesis (hepatic ketone body synthesis)

Ketogenesis is the mitochondrial pathway, operating chiefly in liver during fasting, starvation, prolonged exercise and low-carbohydrate states, that converts acetyl-CoA (mostly from fatty-acid beta-oxidation) into the circulating ketone bodies acetoacetate and (R)-3-hydroxybutyrate, which supply oxidizable fuel to brain, heart and muscle when glucose is scarce. Four mitochondrial-matrix steps: mitochondrial acetyl-CoA acetyltransferase (thiolase, ACAT1) condenses two acetyl-CoA to acetoacetyl-CoA; the rate-limiting, fasting-induced mitochondrial HMG-CoA synthase (HMGCS2) adds a third acetyl-CoA to give 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA); HMG-CoA lyase (HMGCL) cleaves HMG-CoA to acetoacetate + acetyl-CoA; and the inner-membrane NAD+-dependent D-3-hydroxybutyrate dehydrogenase (BDH1) reversibly reduces acetoacetate to (R)-3-hydroxybutyrate, the predominant blood ketone. The pathway shares the HMGCL step with leucine catabolism and shares BDH1 (run in reverse) with ketolysis; liver exports the ketone bodies because it lacks the ketolytic enzyme OXCT1/SCOT. Inherited defects: HMGCS2 deficiency and HMGCL deficiency cause fasting hypoketotic hypoglycemia; ACAT1 (beta-ketothiolase) deficiency affects both ketone-body and isoleucine metabolism. (Ketone-body UTILIZATION/ketolysis in peripheral tissues — BDH1 -> OXCT1 -> ACAT1 -> 2 acetyl-CoA — is modelled separately in MODULE:ketone_body_oxidation.)