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