Acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, is regulated at multiple levels. A drug that mimics the effect of glucagon on hepatic ACC would have which mechanism of action?

• A Dephosphorylation of ACC via protein phosphatase 2A, activating the enzyme
• B Increased citrate concentration in cytoplasm, polymerizing and activating ACC
• C Phosphorylation of ACC via protein kinase A (PKA), inactivating the enzyme ✓
• D Decreased malonyl-CoA levels, relieving CPT-I inhibition and activating ACC

Explanation

Glucagon raises cAMP, activating PKA. PKA phosphorylates ACC at serine residues, causing its dissociation from the active polymeric filament into inactive dimers — thereby inhibiting fatty acid synthesis. This is the opposite of insulin's effect (which activates phosphatase to dephosphorylate ACC). AMPK also phosphorylates ACC (same residue as PKA) during energy depletion. Citrate activates ACC allosterically, and the result of ACC inhibition is reduced malonyl-CoA, which relieves CPT-I inhibition and promotes beta-oxidation.

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

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