[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Ketogenesis (ketone body synthesis)

[Biochemistry](https://durgical.com/en/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

## Interactive map

## Key facts

- 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.

## In detail

- 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.

**Also called**
Ketone body synthesis, Ketogenesis and ketolysis

## Regulation

- 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.

## The steps, one by one

- **Step 1 · Mitochondrial acetoacetyl-CoA thiolase (ACAT1, T2)** [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) + [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) ⇌ Acetoacetyl-CoA + coenzyme A Joins 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)](https://durgical.com/en/biochemistry/enzymes/mitochondrial-hmg-coa-synthase/)** irreversible Acetoacetyl-CoA + [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) + H₂O → HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) + coenzyme A Rate-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](https://durgical.com/en/biochemistry/molecules/acetoacetate/) + [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) Splits 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)](https://durgical.com/en/biochemistry/enzymes/hydroxybutyrate-dehydrogenase/)** [Acetoacetate](https://durgical.com/en/biochemistry/molecules/acetoacetate/) + NADH ⇌ [β-Hydroxybutyrate](https://durgical.com/en/biochemistry/molecules/hydroxybutyrate/) + [NAD⁺](https://durgical.com/en/biochemistry/molecules/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 →](https://durgical.com/en/conditions/diabetic-ketoacidosis/)

## Clinical notes

- 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.

## Pathways

- [Fatty acid β-oxidation](https://durgical.com/en/biochemistry/pathways/fatty-acid-oxidation/)
- [Krebs cycle (citric acid cycle)](https://durgical.com/en/biochemistry/pathways/krebs-cycle/)

## Related conditions

- [Diabetic ketoacidosis](https://durgical.com/en/conditions/diabetic-ketoacidosis/)
- [Type 1 diabetes mellitus](https://durgical.com/en/conditions/type-1-diabetes-mellitus/)
- [Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency](https://durgical.com/en/conditions/medium-chain-acyl-coa-dehydrogenase-deficiency/)
- [Jamaican vomiting sickness (ackee poisoning)](https://durgical.com/en/conditions/jamaican-vomiting-sickness/)

## Related

- [Mitochondrial HMG-CoA synthase (HMGCS2)](https://durgical.com/en/biochemistry/enzymes/mitochondrial-hmg-coa-synthase/)
- [β-Hydroxybutyrate dehydrogenase (BDH1)](https://durgical.com/en/biochemistry/enzymes/hydroxybutyrate-dehydrogenase/)
- [Succinyl-CoA:3-ketoacid CoA transferase (SCOT)](https://durgical.com/en/biochemistry/enzymes/succinyl-coa-3-ketoacid-coa-transferase/)
- [Acetoacetate (acetoacetic acid)](https://durgical.com/en/biochemistry/molecules/acetoacetate/)
- [β-Hydroxybutyrate](https://durgical.com/en/biochemistry/molecules/hydroxybutyrate/)
- [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/)
- [Fatty acid β-oxidation](https://durgical.com/en/biochemistry/pathways/fatty-acid-oxidation/)
- [Krebs cycle (citric acid cycle)](https://durgical.com/en/biochemistry/pathways/krebs-cycle/)
- [NAD⁺ (nicotinamide adenine dinucleotide)](https://durgical.com/en/biochemistry/molecules/nad/)
- [HMG-CoA reductase](https://durgical.com/en/biochemistry/enzymes/hmg-coa-reductase/)

## Test yourself

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.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/ketogenesis/)

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

Sources: [Synthesis of Ketone Bodies](https://reactome.org/PathwayBrowser/#/R-HSA-77111) (Reactome, 2026); [Utilization of Ketone Bodies](https://reactome.org/PathwayBrowser/#/R-HSA-77108) (Reactome, 2026); [Ketone body metabolism](https://reactome.org/PathwayBrowser/#/R-HSA-74182) (Reactome, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

[← All of biochemistry](https://durgical.com/en/biochemistry/)

## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake

Representative model, for educational purposes only.

---
Source: https://durgical.com/en/biochemistry/pathways/ketogenesis/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/ketogenesis/