6 min readPathway sheetA 10-mark or 5-mark answer

Ketone bodies

When fat breakdown is high and carbohydrate is low, the liver turns surplus acetyl-CoA into ketone bodies, a water-soluble fuel for other tissues.

The threeAcetoacetate, β-hydroxybutyrate, acetone

Made inLiver mitochondria (ketogenesis)

Control pointHMG-CoA synthase

Used byHeart, muscle, kidney; brain in long fasting. Not liver, not red cells.

Ketogenesis (in liver mitochondria)

Starts from acetyl-CoA made by beta-oxidation. The starred step controls the rate.

1
2 Acetyl-CoA → Acetoacetyl-CoA + CoA
Thiolase
2★
Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA
HMG-CoA synthase · regulatory (rate-limiting) step
3
HMG-CoA → Acetoacetate + Acetyl-CoA
HMG-CoA lyase
4
Acetoacetate + NADH ⇌ β-Hydroxybutyrate
β-Hydroxybutyrate dehydrogenase · reversible
5
Acetoacetate → Acetone + CO2
spontaneous, no enzyme · acetone is breathed out

★ one-way, controls the pace

Ketolysis (in heart, muscle, kidney, brain)

The liver lacks thiophorase, so it makes ketone bodies but cannot use them.

1
β-Hydroxybutyrate → Acetoacetate
β-Hydroxybutyrate dehydrogenase · makes NADH
2★
Acetoacetate + Succinyl-CoA → Acetoacetyl-CoA + Succinate
Thiophorase (succinyl-CoA:acetoacetate CoA transferase) · absent in liver
3
Acetoacetyl-CoA + CoA → 2 Acetyl-CoA
Thiolase · acetyl-CoA enters the TCA cycle

★ one-way, controls the pace

Ketosis vs ketoacidosis

KetosisRaised ketone bodies in the blood (ketonaemia) and urine (ketonuria), with acetone on the breath. Seen in starvation, very low-carbohydrate diets and long exercise. Blood pH stays normal.

KetoacidosisKetone bodies are acids. When they build up enough to lower blood pH, it is ketoacidosis, typical of uncontrolled type 1 diabetes (DKA). Signs: fruity breath, deep fast breathing, dehydration. A medical emergency.

Cause: low insulin and high glucagon speed up fat breakdown, and oxaloacetate is used for gluconeogenesis, so acetyl-CoA cannot enter the TCA cycle.

Ketogenic diet

Very high fat, very low carbohydrate, adequate protein.
Keeps the body in ketosis, so ketone bodies replace much of the glucose as fuel.
Used under medical supervision for epilepsy that does not respond to drugs, especially in children.
Also tried for weight loss; possible problems include constipation, raised blood cholesterol and kidney stones.

Nutrition link

Carbohydrate is antiketogenic: regular meals with enough cereal, pulses or fruit prevent starvation ketosis. In uncontrolled diabetes, low insulin lets fat break down fast and ketone bodies pile up, so diet, insulin and meal timing must match. A ketogenic diet should be followed only under a doctor or dietitian.

Exam angle

10 marks: “Describe the formation and utilisation of ketone bodies. Add a note on ketosis.” Ketogenesis steps with HMG-CoA synthase, ketolysis with thiophorase, why the liver cannot use them, then the causes and effects of ketosis.

5 marks: “Why does ketosis occur in uncontrolled diabetes?” Low insulin raises fat breakdown; oxaloacetate goes to gluconeogenesis, so surplus acetyl-CoA in the liver forms ketone bodies.

2 marks: “Name the ketone bodies.” Acetoacetate, β-hydroxybutyrate and acetone.

Remember it

The liver makes ketone bodies but cannot take them: it lacks thiophorase.