Name of ketone bodies Describe formation and utilisation of ketone bodies

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Ketone Bodies

Names of the Three Ketone Bodies

Ketone Body	Also Known As	Notes
Acetoacetate	Acetoacetic acid	Primary ketone body; the hub of ketone metabolism
Beta-hydroxybutyrate (β-hydroxybutyrate)	D-3-hydroxybutyrate	Quantitatively the most abundant in blood/urine during ketosis; strictly not a "ketone" chemically (it has a hydroxyl group, not a keto group), but classified as a ketone body
Acetone	Dimethyl ketone	Formed by spontaneous, non-enzymatic decarboxylation of acetoacetate; volatile, excreted via lungs

The interrelationship of these three is shown below:

Interrelationships of the ketone bodies - Harper's Fig. 22-5

Formation of Ketone Bodies (Ketogenesis)

Site: Exclusively in the hepatic mitochondrial matrix (and rumen epithelium in ruminants). Extrahepatic tissues lack the necessary enzymes (particularly mitochondrial HMG-CoA synthase) to produce ketone bodies.

Conditions that trigger ketogenesis:

Prolonged fasting / starvation
Uncontrolled diabetes mellitus (low insulin : glucagon ratio)
High-fat, low-carbohydrate diet
Prolonged heavy exercise

Step-by-Step Pathway

Synthesis of ketone bodies - Basic Medical Biochemistry Fig. 30.17

Step 1 - Acetoacetyl-CoA formation Two molecules of acetyl-CoA (generated from beta-oxidation of fatty acids) condense via thiolase (reversal of the beta-oxidation thiolase reaction) to form acetoacetyl-CoA, releasing one CoA-SH.

Step 2 - HMG-CoA formation Acetoacetyl-CoA condenses with another acetyl-CoA via HMG-CoA synthase (the rate-limiting, key regulatory enzyme of ketogenesis) to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), releasing CoA-SH.

Step 3 - Acetoacetate release HMG-CoA lyase cleaves HMG-CoA, releasing acetyl-CoA and free acetoacetate. Both HMG-CoA synthase and HMG-CoA lyase must be present in the mitochondria for ketogenesis to occur.

Step 4 - From acetoacetate, two fates:

Reduction to beta-hydroxybutyrate: acetoacetate is reduced by mitochondrial D-3-hydroxybutyrate dehydrogenase using NADH + H⁺ → NAD⁺. The equilibrium between the two is controlled by the NAD⁺/NADH redox state of the mitochondria. During heavy beta-oxidation, NADH is abundant, so the ratio of beta-hydroxybutyrate : acetoacetate shifts toward ~3:1.
Spontaneous decarboxylation to acetone: non-enzymatic, losing CO₂. Acetone is excreted via the lungs.

Regulation of Ketogenesis

Increased free fatty acid supply from adipose tissue (lipolysis activated by glucagon/low insulin)
Decreased insulin inactivates acetyl-CoA carboxylase → decreased malonyl-CoA → releases inhibition of CPT-1 (carnitine palmitoyltransferase I) → fatty acyl-CoA enters mitochondria for beta-oxidation
High NADH/NAD⁺ ratio inhibits the TCA cycle (oxaloacetate is diverted to malate/gluconeogenesis), so acetyl-CoA cannot enter the TCA cycle and is redirected to ketogenesis
Increased transcription of mitochondrial HMG-CoA synthase gene during prolonged fasting

Utilisation of Ketone Bodies

Site: All extrahepatic tissues (brain, heart, skeletal muscle, renal cortex, intestinal mucosa, etc.) except liver and red blood cells.

The liver produces ketone bodies but cannot utilize them - it lacks succinyl-CoA transferase (CoA transferase / thiophorase), the key enzyme for ketone reactivation. This ensures a net outflow of ketone bodies from liver to peripheral tissues.

The overall flow is illustrated below:

Formation, utilization, and excretion of ketone bodies - Harper's Fig. 22-6

Step-by-Step Utilization Pathway

Step 1 - Beta-hydroxybutyrate → Acetoacetate In extrahepatic tissue mitochondria, beta-hydroxybutyrate is oxidized back to acetoacetate by D-3-hydroxybutyrate dehydrogenase, producing NADH.

Step 2 - Reactivation of acetoacetate (key step) Acetoacetate receives CoA from succinyl-CoA via succinyl-CoA-acetoacetate-CoA transferase (thiophorase). This yields acetoacetyl-CoA and succinate. This reaction is absent in the liver (ensuring net ketone body export).

Step 3 - Thiolase cleavage Acetoacetyl-CoA is cleaved by thiolase (3-ketothiolase) to yield 2 molecules of acetyl-CoA.

Step 4 - TCA cycle oxidation The two acetyl-CoA molecules enter the citric acid cycle and are oxidized to CO₂ and H₂O, generating ATP.

ATP yield:

1 mol acetoacetate → ~19 mol ATP
1 mol beta-hydroxybutyrate → ~21.5 mol ATP (extra NADH from the dehydrogenase step)

Tissues and Context

Tissue	Ketone Body Use
Brain	Uses extensively during prolonged starvation (replaces ~2/3 of glucose needs)
Skeletal muscle	Active user during fasting and exercise
Heart	Preferential fuel; uses ketones over glucose when available
Renal cortex	Major ketone consumer
Intestinal mucosa	Uses ketones + amino acids (not fatty acids) during starvation
Fetus	Ketone bodies cross the placenta and are used as fuel
Adipocytes	Can use ketones but not fatty acids during fasting
Liver	Produces but cannot utilize ketone bodies
RBCs	Cannot use (lack mitochondria)

Normal Blood Levels and Clinical Significance

State	Total ketone body concentration
Well-fed	< 0.2 mmol/L
Prolonged fasting	4-5 mmol/L
Ketoacidosis threshold	> 7 mmol/L (exceeds bicarbonate buffer, causes acidosis and Kussmaul respiration)
Oxidative machinery saturation	~12 mmol/L

During uncontrolled type 1 diabetes, the relative excess of glucagon (a potent stimulator of ketogenesis) combined with increased fatty acid supply markedly elevates ketone body formation. Utilization fails to keep pace, leading to diabetic ketoacidosis (DKA).

Sources: Harper's Illustrated Biochemistry, 32nd Ed, pp. 232-233; Basic Medical Biochemistry - A Clinical Approach, 6th Ed, pp. 1097-1103

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