Ketone Bodies

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

Ketone Bodies

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