ketone body formation

Meaning: Liver mitochondria condense two acetyl-CoA into acetoacetyl-CoA, add a third to make HMG-CoA (HMG-CoA synthase, the regulated step), then HMG-CoA lyase releases acetoacetate. Acetoacetate is reduced by an NADH-dependent step to β-hydroxybutyrate, or it loses CO₂ spontaneously to form acetone. Fasting, prolonged exercise and low insulin with high glucagon drive it: fatty acid oxidation floods the liver with acetyl-CoA, and oxaloacetate is diverted to gluconeogenesis, so the citric acid cycle cannot take up all of it. Ketone bodies travel in blood to the brain, heart and skeletal muscle, where they are converted back to acetyl-CoA. The liver lacks the enzyme needed to do this, so it exports them without using them.

On the MCAT: A passage describes starvation, a low-carbohydrate diet or uncontrolled diabetes mellitus. You predict that fat oxidation and blood ketone levels rise, and that blood pH falls because acetoacetate and β-hydroxybutyrate are acids. You may be asked which tissues use ketones. Red blood cells cannot, because they have no mitochondria.

Common confusion: Ketogenesis and cholesterol synthesis both use HMG-CoA, but they are separate pathways. Ketogenesis is mitochondrial and uses HMG-CoA synthase and lyase. Cholesterol synthesis is cytosolic and its regulated enzyme is HMG-CoA reductase. Also, animals cannot make net glucose from fatty acids, which is why ketones serve as the brain's alternative fuel.