Ketone Metabolism Lecture

When Does the Body Use Ketones?

• Ketones are not the preferred energy source
• Used in certain conditions:
  • Low blood glucose levels
  • Prolonged starvation
  • Uncontrolled Type 1 Diabetes
  • Carbohydrate-restricted diets (e.g., Atkins diet)

Why These Conditions Trigger Ketone Use?

• Low Blood Glucose:
  • Brain typically uses glucose
  • In low glucose conditions, the brain and muscles use ketone bodies therefore are sites for ketolysis

Ketogenesis

• Location: Occurs primarily in the liver
• Process:
  • Glucose is normally oxidized to pyruvate, then to acetyl CoA
  • Acetyl CoA combines with oxaloacetate to form citrate, entering the Krebs cycle
  • Low glucose results in low pyruvate, low acetyl CoA, reducing Krebs cycle activity
  • Beta-oxidation of fatty acids provides acetyl CoA
  • If oxaloacetate is used for gluconeogenesis, acetyl CoA levels rise
  • Excess acetyl CoA initiates ketogenesis

Steps in Ketone Body Formation

1. Acetyl CoA Fuses: Forms acetoacetyl CoA
   • Enzyme: * thiolase
2. HMG CoA Formation(3 hydroxy 3 methyl glutaro coA)
   • Acetoacetyl CoA + Acetyl CoA = HMG CoA
   • Enzyme: HMG CoA synthase (Rate-limiting step)
3. Conversion to Acetoacetate
   • Enzyme: HMG CoA lyase
   • Acetoacetate can enter the blood or convert to beta-hydroxybutyrate
   • Beta-hydroxybutyrate
     • Enzyme: **Beta-hydroxybutyrate

dehydrogenase**

Ketone Bodies in the Blood

• Types: Acetoacetate and Beta-hydroxybutyrate
• Utilized by muscles and brain

Acidosis and Other Complications in diabetic keto acidosis and prolonged starvation.

• Acetone formation from acetoacetate, (by acetoacetate decarboxylase) causing fruity breath
• Acidosis due to acidic ketones (pKa ~4-5)
• High anion gap (>11 mM) indicates acidosis
• Symptoms:
  • Fruity breath
  • Kussmaul breathing (hyperventilation)
  • Vomiting -> Hypovolemia -> Possible coma
  • Ketoacidosis could lead to keto uria (ketones in urine)

Energy Utilization

• Reverse reaction in muscles/brain:
  • Convert beta-hydroxybutyrate to acetoacetate by enzyme beta hydroxide buterate dehydrogenase
  • Convert acetoacetate to acetoacetyl CoA by enzyme “thiophorase”(or acetoacetate succinyl coA transferase)
  • Ultimately form acetyl CoA for Krebs cycle by enzyme acetyl coA acyl transferase(thiolase)
• ATP production via electron transport chain

Hormone: glucagon stimulates it and insulin inhibits

Conclusion

• Ketone metabolism is an adaptive mechanism for energy production under specific conditions
• The brain can utilize ketones due to the ability to cross the blood-brain barrier
• Important in medical diagnosis and treatment of metabolic conditions