Ketolysis
Extrahepatic tissues convert ketone bodies back into acetyl-CoA for oxidation by the TCA cycle. The reverse of ketogenesis, except in a different tissue.
The Pathway (in Extrahepatic Tissues)
- Beta-hydroxybutyrate + NAD+ → acetoacetate + NADH (BHB dehydrogenase).
- Acetoacetate + succinyl-CoA → acetoacetyl-CoA + succinate (thiophorase, also called succinyl-CoA:acetoacetate CoA transferase). This enzyme is ABSENT in liver.
- Acetoacetyl-CoA + CoA → 2 acetyl-CoA (thiolase).
- Acetyl-CoA enters the TCA cycle.
Who Uses Ketones
- Brain: after 3-4 days of fasting, ketones supply up to 60-75 percent of brain energy.
- Heart: always uses ketones when available; the heart is surprisingly flexible in fuel choice.
- Skeletal muscle: uses ketones during fasting.
- Kidney cortex: uses ketones.
- Liver: makes ketones but cannot use them (no thiophorase).
- RBCs: do not use ketones (no mitochondria).
How is beta-hydroxybutyrate converted back into acetyl-CoA for use?
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BHB + NAD+ → acetoacetate + NADH. Then thiophorase (succinyl-CoA:acetoacetate CoA transferase) transfers CoA from succinyl-CoA to acetoacetate, producing acetoacetyl-CoA. Thiolase then cleaves acetoacetyl-CoA to 2 acetyl-CoA, which enter the TCA cycle. Thiophorase is missing in the liver, which is why the liver cannot use ketones.
What tissues can use ketone bodies as fuel, and what tissue cannot?
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Brain, heart, skeletal muscle, kidney cortex, and many other tissues with mitochondria and thiophorase use ketones. Red blood cells cannot (no mitochondria). The liver itself cannot (no thiophorase - this is the reason the liver can make but not use ketones). The brain increasingly shifts to ketones during prolonged fasting, supplying up to 75% of its energy.
Why is ketone body utilization important for survival in prolonged starvation?
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The brain depends primarily on glucose and cannot use fatty acids directly. If ketones were unavailable, the body would have to break down muscle protein at a high rate to make glucose via gluconeogenesis - rapidly depleting protein reserves. Ketones let the brain use an alternative fuel derived from fat stores, sparing muscle protein and dramatically extending survival. After 3-4 days of fasting, ketones supply ~60-75% of brain energy.