During prolonged starvation (beyond 5–7 days), the brain adapts its fuel utilisation by switching from glucose to ketone bodies. The biochemical signal that initiates hepatic ketogenesis during fasting is:

• A High cortisol directly activates HMG-CoA synthase in mitochondria
• B Elevated glucagon directly phosphorylates and inhibits malonyl-CoA decarboxylase
• C Low insulin:glucagon ratio activates adipose triglyceride lipase, raising free fatty acid delivery to liver; intramitochondrial acetyl-CoA exceeds OAA capacity ✓
• D Low blood glucose inhibits CPT-I through AMP-kinase, diverting acetyl-CoA to ketogenesis

Explanation

During starvation, low insulin and high glucagon decrease malonyl-CoA (the allosteric inhibitor of CPT-I). This allows long-chain fatty acyl-CoA entry into mitochondria via CPT-I. Simultaneously, oxaloacetate (OAA) is depleted by gluconeogenesis, so acetyl-CoA cannot enter the TCA cycle and instead condenses via mitochondrial HMG-CoA synthase to form ketone bodies. The low insulin:glucagon ratio is the master regulator initiating all these metabolic shifts.

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

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