Metabolism of Ketone Bodies

1. Ketone Metabolism
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Acetone, Acetoacetate &
β-hydroxybutyrate

2. Ketone Bodies Metabolism
• Ketone synthesis occurs in
the Liver - Mitochondria
• During prolonged starvation,
fasting (and in diabetes)
oxaloacetate is depleted in
liver due to gluconeogenesis
• This impedes entry of
acetyl-CoA into Krebs cycle.
• Acetyl-CoA in liver
mitochondria is converted
then to ketone bodies -
Acetone, Acetoacetate &
β-hydroxybutyrate.
Glucose-6-phosphatase
glucose-6-P glucose
Gluconeogenesis Glycolysis
pyruvate
fatty acids
acetyl CoA ketone bodies
cholesterol
oxaloacetate citrate
Krebs Cycle

3. KETOGENESIS
(Regulatory enzyme)

4. KETOGENESIS
Acetyl CoA
C-Skeleton of Ketogenic Amino
acids (E.g. Leucine, Ala, Phe)

5. Formation
of
Ketone bodies
(KETOGENESIS)
Hormone effect
- Glucagon stimulate
- Insulin inhibits
(Regulatory enzyme)

6. Functions
• Ketone bodies are transported from the
liver to Extra hepatic tissues (E.g. Muscles),
where they are converted back to Acetyl-
CoA - catabolism in Krebs cycle, to
generate ATP.
• An alternative fuel
– for heart, kidney & Muscle.
– Prolonged starvation – for the Brain also

7. Re-utilization
of
Ketone bodies
(KETOLYSIS)

8. OVER PRODUCTION OF
KETONE BODIES
• KETONEMIA – increased in the blood
• KETONURIA -increased in the urine
• KETOSIS -increased in the tissues
– Smell of Acetone in the breath
• KETOACIDOSIS
• CAUSES –starvation & uncontrolled DM
• TREATMENT
– Administration of Insulin
– Correct the metabolic abnormalities & the
associated water and Electrolyte imbalance

9. Clinical Significance of Ketogenesis
• Carbohydrate shortages cause the liver to increase
Fatty acid oxidation Acetyl-coA Ketone bodies
• Ketone bodies serve as a energy source for Heart
Renal cortex and Skeletal muscles, thereby
preserving the limited glucose for use by the brain.
• ↑Mainly in Starvation & untreated insulin-dependent
diabetes mellitus [diabetic ketoacidosis (DKA)].
• Ketone bodies increase lowers the pH of the blood.
• Acidification of the blood is dangerous chiefly
because it impairs the ability of hemoglobin to
bind oxygen ---- results in coma & even death.

10. LIPIDS: CHOLESTEROL
METABOLISM
AND METABOLISM

11. MITOCHONDRION
Fatty acids
oxaloacetate
(2) Acetyl CoA
b-oxidation
Thiolase
Acetoacetyl CoA
OAAmalatepyruvate+NADPH
Citrate Citrate
HMG CoA synthase
HMG CoA
HMG CoA lyase
Acetoacetate b-Hydroxybutyrate
Ketone bodies
(only synthesized in liver)
malic enzyme
Lyase (requires ATP)
(2) Acetyl CoA
Thiolase
Acetoacetyl CoA
HMG CoA
Statins
Mevalonate
CHOLESTEROL
smooth
endoplasmic
reticulum
HMG CoA
reductase
cytoplasm
HMG-CoA
synthase
Figure 1. Synthesis of HMG-CoA in mitochondria (ketone bodies) and cytoplasm (cholesterol)

12. Stage 1
NADPH
NADP+
Stage 2
Mevalonate
3ATP
CO2
Several
Condensation Steps
3ADP
Active Isoprenoids (C5)
NADPH
NADP+
Squalene (C30)
rate-determining step
cholesterol activates proteolytic degradation
amount controlled by induction/repression
hormonally controlled via phosphorylation
Stage 3
Squalene (C30)
Cyclization
Squalene
epoxidase/
cyclase
O2
NADPH
NADP+
Lanosterol (C30)
(4-ring structure)
Stage 4
Lanosterol (C30)
O (19 steps) 2
NADPH
NADP+ 3 CH3
Cholesterol (C27)
Acetyl CoA (C2)
HMG-CoA
HMG-CoA
Reductase
Mevalonate (C6)
Figure 2. The four stages of cholesterol biosynthesis

13. FATES OF CHOLESTEROL
Membrane structure
Precursor of steroid hormones and vitamin D
Esterification for storage
Esterification for elimination
Precursor to bile salts

14. CITRIC
ACID
CYCLE
GGllyycceerrooll Fatty Acids
2 CO2
Phospholipids
ACS
Li
poge
nesi
s
Lipolysis
Triacylglycerol
Phosphatidic Acid
Glycerol-P
Esterification
Steroids
Steroidogenesis
Ketone
Bodies
Fatty Acyl-CoA
b-Oxidation
Cholesterol
Cholesterogenesis
Glucose Pyruvate Acetyl-CoA
Glycolysis
Ketogenesis
Figure 1. Interactions of lipid metabolic pathways