During prolonged fasting, hepatic ketogenesis increases. The key committed step in ketogenesis is catalysed by HMG-CoA synthase 2 (mitochondrial). Which mechanism prevents ketone body utilisation by the liver itself?

• A The liver lacks HMG-CoA lyase, preventing conversion of HMG-CoA to acetoacetate
• B The liver lacks succinyl-CoA:3-oxoacid CoA transferase (SCOT / 3-oxoacid CoA transferase), the enzyme needed to activate acetoacetate to acetoacetyl-CoA for oxidation ✓
• C Ketone bodies are exported as soon as they form because they are toxic to hepatocytes at any concentration
• D Mitochondrial beta-hydroxybutyrate dehydrogenase is absent from hepatocytes

Explanation

Acetoacetate and beta-hydroxybutyrate synthesised by the liver are exported for use by extrahepatic tissues (brain, heart, skeletal muscle, kidney cortex). Activation of acetoacetate for oxidation requires SCOT (succinyl-CoA:3-oxoacid CoA transferase), which transfers CoA from succinyl-CoA to acetoacetate forming acetoacetyl-CoA. Hepatocytes express SCOT at negligible levels, so the liver cannot oxidise its own ketone bodies — a teleologically sensible arrangement that preserves ketone bodies for glucose-deprived tissues. This is distinct from the synthetic capacity: liver has HMG-CoA synthase 2 (mitochondrial) for ketogenesis, while extrahepatic tissues use SCOT for ketone utilisation.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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