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Ketone Bodies

Ketone Bodies

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KETOGENESIS
  • Ketone bodies synthesized in liver only (mitochondrial matrix)
  • Occurs under 2 clinical conditions: prolonged starvation & uncontrolled diabetes
  • Substrate: excess acetyl CoA (derived from fatty acid oxidation)
  • Normal, healthy adult: excess acetyl CoA shunts to citric acid cycle or cholesterol biosynthesis
KETONE BODIES 1. Acetoacetate 2. Acetone
  • Volatile
  • Breathed out unused
3. Beta-hydroxybutyrate
KETOGENIC PATHWAY
  • Fasting conditions (starvation or uncontrolled diabetes)
1. Oxaloacetate shunts into gluconeogenesis: slows down citric acid cycle 2. Acetyl CoA builds up and shunts into ketogenesis 3. 2 Acetyl CoA --> Acetoacetyl CoA (acetoacetyl CoA thiolase, reversible) 4. 1 Acetyl CoA + Acetoacetyl CoA --> HMG CoA (HMG CoA synthase)
  • Thiolase & HMG CoA synthase also in cholesterol biosynthesis (ketogenic isozymes in matrix not cytosol)
5. HMG CoA --> Acetyl CoA + Acetoacetate (HMG CoA lyase) 6. Acetoacetate + NAD+ --> beta-hydroxybutyrate + NADH (beta-hydroxybutyrate dehydrogenase, reversible)
KETOSIS
  • Spontaneous when [acetoacetate] is high
  • Acetoacetate --> Acetone + CO2
RATE LIMITING STEP
  • HMG CoA synthase: enzyme localized in liver
  • Activated by: fasting, increased cAMP and increased lipolysis
  • Inhibited by: feeding & insulin
TARGET CELL KETONE BODY USE
  • Cells that can use ketone bodies
  • Include: cardiac/skeletal muscle, renal cortex, intestinal mucosa, brain cells in starvation
  • Ketone bodies can cross blood brain barrier: do NOT bind albumin (fatty acids do)
  • Mobilized in matrix
Enzyme beta-ketoacyl CoA transferase
  • NOT in liver (liver cannot mobilize ketone bodies)
  • Acetoacetate + succinyl CoA --> acetoacetyl CoA + succinate (reversible)
  • Remaining reactions are the reverse of ketogenesis
CLINICAL CORRELATION
Untreated diabetics
  • Have fruity breath due to exhalation of acetone (ketosis)
  • Decreased cellular glucose and CAC intermediates leads to inc. FA mobilization & acetyl CoA
  • Excess acetyl CoA shunts into ketogenesis

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