In the fasted state, hepatic ketogenesis is activated. Which enzyme controls the committed step of ketogenesis, and what regulates its activity?

• A HMG-CoA reductase — inhibited by statins
• B Thiolase — inhibited by acetoacetyl-CoA
• C Carnitine palmitoyl transferase-1 — activated by malonyl-CoA
• D HMG-CoA synthase (mitochondrial) — induced by glucagon/low insulin state and activated by acetyl-CoA availability ✓

Explanation

Ketogenesis proceeds: 2 acetyl-CoA → acetoacetyl-CoA (thiolase) → HMG-CoA (mitochondrial HMG-CoA synthase) → acetoacetate + acetyl-CoA (HMG-CoA lyase) → beta-hydroxybutyrate. The rate-limiting step is mitochondrial HMG-CoA synthase (distinct from cytosolic HMG-CoA reductase). It is induced transcriptionally by PPARalpha (activated by fatty acid ligands during fasting) and increased substrate acetyl-CoA from beta-oxidation drives the reaction forward. Glucagon suppresses malonyl-CoA (by inactivating acetyl-CoA carboxylase), allowing CPT-1 activity and beta-oxidation to proceed — the prerequisite for ketogenesis.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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