U01.01.120 Ketone bodies

In the liver, fatty acids and amino acids are metabolized to form ketone bodies, primarily acetoacetate, and β-hydroxybutyrate, which are used by extrahepatic tissues such as muscle and brain during prolonged periods of fasting or stress. In conditions like prolonged starvation or diabetic ketoacidosis, the depletion of oxaloacetate for gluconeogenesis leads to an increased production of ketone bodies.

Key Processes Involved in Ketone Body Formation

Fatty Acid and Amino Acid Metabolism:
- Fatty acids and amino acids are broken down to form acetyl-CoA, which enters ketogenesis.
Acetoacetate and β-Hydroxybutyrate Formation:
- Acetoacetate is converted to β-hydroxybutyrate or can be further decarboxylated to form acetone.
Regulation of Oxaloacetate:
- In prolonged starvation or diabetic ketoacidosis, oxaloacetate is used for gluconeogenesis, which decreases its availability for the TCA cycle, promoting the formation of ketone bodies.
- In alcoholism, NADH production from alcohol metabolism shunts oxaloacetate to malate, further inhibiting the TCA cycle.
Ketone Body Usage:
- Ketone bodies like acetoacetate and β-hydroxybutyrate are transported to extrahepatic tissues (muscle and brain) for energy.
- Acetone expires via the lungs and contributes to the characteristic fruity odor of breath.

Key Enzymes

HMG-CoA Lyase: Catalyzes the formation of acetoacetate from HMG-CoA during ketogenesis.
HMG-CoA Reductase: Involved in the synthesis of cholesterol, not ketones.

Summary Table: Ketone Body Metabolism

Metabolic Process	Key Enzyme	Key Products	Location
Fatty Acid and Amino Acid Metabolism	Acetyl-CoA formation	Acetyl-CoA	Liver
Ketogenesis	HMG-CoA Lyase	Acetoacetate, β-hydroxybutyrate, Acetone	Liver
Ketone Utilization	–	Acetoacetate, β-hydroxybutyrate	Extrahepatic tissues (muscle, brain)
Alcoholism Impact	NADH accumulation	Shifts oxaloacetate to malate	Liver

Points to Remember for USMLE Step 1 Preparation

Ketone Bodies:
- The three major ketone bodies are acetone, acetoacetate, and β-hydroxybutyrate.
- Ketone bodies are primarily used by extrahepatic tissues like muscles and the brain during prolonged fasting.
- RBCs cannot use ketones and rely solely on glucose for energy.
Conditions that Increase Ketogenesis:
- Prolonged starvation or diabetic ketoacidosis leads to a depletion of oxaloacetate, enhancing ketone body production.
- In alcoholism, excess NADH prevents oxaloacetate from entering the TCA cycle, promoting ketone formation.
Detection of Ketone Bodies:
- Acetoacetate can be detected in urine with a ketone test, but β-hydroxybutyrate cannot.
- Acetone contributes to the fruity odor in the breath, commonly associated with diabetic ketoacidosis.

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