Biochemistry · Metabolic pathway

Ketogenesis (ketone body synthesis) !

During fasting or without insulin, the liver turns surplus acetyl-CoA into ketone bodies, a fuel the brain and heart can use.

Updated 2026-11-01

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Only in liver mitochondria; the rate-limiting step is mitochondrial HMG-CoA synthase (HMGCS2).
Ketone bodies: acetoacetate, β-hydroxybutyrate (the most abundant) and acetone (volatile, breathed out).
The liver cannot use them: it lacks succinyl-CoA transferase (SCOT), so it exports them.
Ketolysis in tissues: β-hydroxybutyrate → acetoacetate → acetoacetyl-CoA (SCOT, takes CoA from succinyl-CoA) → 2 acetyl-CoA.
In prolonged fasting the brain can get about two thirds of its energy from ketones.

Trigger: low insulin and high glucagon release fatty acids from adipose tissue.
In the liver β-oxidation produces more acetyl-CoA than the Krebs cycle can burn, because oxaloacetate is diverted to gluconeogenesis.
Spare acetyl-CoA condenses into acetoacetyl-CoA and HMG-CoA, which the lyase splits into acetoacetate.
Some acetoacetate is reduced to β-hydroxybutyrate and a small part loses CO₂ on its own to form acetone.
Muscle, heart, kidney and brain activate acetoacetate with SCOT and burn it in the Krebs cycle.

The insulin/glucagon ratio is the main switch: insulin slows lipolysis and HMGCS2.
Low malonyl-CoA (fasting) opens CPT-I and lets fatty acids into the liver.
Ketones themselves stimulate a little insulin secretion, a brake that is missing in type 1 diabetes.

Step 1 · Mitochondrial acetoacetyl-CoA thiolase (ACAT1, T2) Acetyl-CoA + Acetyl-CoA ⇌ Acetoacetyl-CoA + coenzyme AJoins two acetyl-CoA into acetoacetyl-CoA (4 C): β-oxidation thiolysis run backwards.If it fails: Its deficiency (β-ketothiolase) causes ketoacidotic crises because ketone and isoleucine use also fail.
Step 2 · Mitochondrial HMG-CoA synthase (HMGCS2) irreversible Acetoacetyl-CoA + Acetyl-CoA + H₂O → HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) + coenzyme ARate-limiting step: adds a third acetyl-CoA and forms HMG-CoA (6 C) inside liver mitochondria.If it fails: Its deficiency causes hypoketotic hypoglycaemia on fasting, much like β-oxidation defects.
Step 3 · HMG-CoA lyase (HMGCL) irreversible HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) → Acetoacetate + Acetyl-CoASplits HMG-CoA into acetoacetate, the first ketone body, and releases one acetyl-CoA.If it fails: Its deficiency blocks ketogenesis and the end of leucine breakdown: hypoglycaemia without ketones and acidosis.
Step 4 · β-Hydroxybutyrate dehydrogenase (BDH1) Acetoacetate + NADH ⇌ β-Hydroxybutyrate + NAD⁺Reduces acetoacetate to β-hydroxybutyrate with NADH; the ratio follows the mitochondrial NADH/NAD⁺.If it fails: In diabetic ketoacidosis β-hydroxybutyrate predominates, and the nitroprusside urine strip does not detect it. Diabetic ketoacidosis →

Diabetic ketoacidosis appears when insulin is lacking: very high ketones, anion-gap acidosis and fruity (acetone) breath.
Ketosis from fasting or a ketogenic diet is mild and causes no major acidosis while some insulin is present.
Alcohol can cause alcoholic ketoacidosis, with much β-hydroxybutyrate and little acetoacetate.
β-Oxidation defects cause hypoglycaemia with inappropriately low ketones.

Think of the answer, then tap the question to see it.

What is the rate-limiting enzyme of ketogenesis and where does it work?

Mitochondrial HMG-CoA synthase (HMGCS2), in liver mitochondria.

Why does the liver make ketones but not use them?

It lacks succinyl-CoA:3-ketoacid CoA transferase (SCOT), which is needed to activate acetoacetate.

Which ketone body does the nitroprusside strip miss?

β-Hydroxybutyrate; the strip detects acetoacetate (and some acetone), so it can underestimate ketosis.

How does the ketogenic HMG-CoA synthase differ from the cholesterol one?

The ketone one is mitochondrial (HMGCS2); the cholesterol one is cytosolic (HMGCS1) and its HMG-CoA goes to HMG-CoA reductase.

Educational information, not medical advice. For any symptom, see a health professional.

Sources: Synthesis of Ketone Bodies (Reactome, 2026); Utilization of Ketone Bodies (Reactome, 2026); Ketone body metabolism (Reactome, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.