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