ketogenesis

Ketogenesis is a hepatic metabolic pathway that produces ketone bodies, primarily in liver mitochondria, in response to low carbohydrate availability or insulin deficiency. It serves as a mechanism to supply energy to tissues such as the brain, heart, and skeletal muscle when glucose is scarce.

The process begins with fatty acids released from adipose tissue and transported to the liver, where they are oxidized to acetyl-CoA. When oxaloacetate is diverted toward gluconeogenesis during fasting or carbohydrate restriction, acetyl-CoA accumulation favors ketogenesis over entry into the TCA cycle. Acetyl-CoA molecules are condensed by the enzyme HMG-CoA synthase 2 to form HMG-CoA, which is then cleaved by HMG-CoA lyase to yield acetoacetate. Acetoacetate can be reduced to beta-hydroxybutyrate by beta-hydroxybutyrate dehydrogenase, using NADH, or it may spontaneously decarboxylate to acetone. The released ketone bodies, acetoacetate and beta-hydroxybutyrate, are released into the bloodstream and transported to peripheral tissues.

In target tissues, ketone bodies are converted back to acetyl-CoA and funneled into the TCA cycle for energy production. Ketogenesis is regulated by hormonal and metabolic factors: insulin inhibits lipolysis and ketogenesis, while glucagon, catecholamines, and fatty acid availability promote it. Transcriptional regulators such as PPARα and the cellular NAD+/NADH ratio also influence the process.

Clinical relevance includes ketoacidosis, a potentially dangerous condition arising from excessive ketone production in settings of insulin deficiency or prolonged fasting, notably in type 1 diabetes. Ketone bodies also function as alternative energy substrates during starvation and are a focus of therapeutic approaches such as ketogenic diets and exogenous ketone administration. Ketogenesis is distinct from ketolysis, the downstream utilization of ketone bodies by peripheral tissues.