Metabolism of Ketone Bodies

(Ketogenesis and Ketolysis)

Ketone bodies are acetoacetate, β-hydroxybutyrate and acetone.

Ketogenesis
Defnition:Synthesis of ketone bodies from acetyl CoA resulting
mainly from the oxidation of fatty acids (and to a much lesser extent
ketogenic amino acids).
Site: occurs in the mitochondria of theliver because of the presence
of HMG-CoA synthase and HMG-CoA lyasechiefly in the liver.
The building unit of ketone bodies is acetyl-CoA derived mainly
from oxidation of fatty acids.
Steps:
- Acetone is volatile and so expired by the lungs. Ketone bodiesare
also excreted in urine.

Importance of Ketone Bodies

- Ketone bodiesgo to exta hepatic tissues to be oxidised into CO2 and
H2O.
- Ketone bodies are important sources of energy for the peripheral
tissues because they are soluble in aqueous solution and, therefore, do
not need to be incorporated into lipoproteins or carried by albumin as
do the other lipids.
- They are of great importance during starvation when fat represents
the main source of energy.
- Although most tissues can utilize fatty acids,they can utilize ketone
bodies more easily.
- During prolonged fasting, the brain cells adapts to utilize ketone
bodies as it cannot utilize fatty acids (fatty acids are bound to plasma
albumin and cannot pass the blood brain barrier).
- It also reduces the need for gluconeogenesis and the breakdown of
tissue proteins.
 Steps of Ketogenesis

Acyl- CoA CH3- CO ~ S – CoA Ketogenic

Acetyl-CoA Amino acids
-Oxidation Acetyl-CoA

-Oxidation Ketothiolase
Last C4
CoA-SH
CH3- CO ~ CH2 - CO ~ S – CoA
Acetoacetyl-CoA
CH3- CO ~ S – CoA
HMG-CoA Synthase Acetyl-CoA
H2O
(Liver mitochondria)
CoA-SH
OH
CH3- C - CH2 - CO ~ S – CoA
CH2 - COOH
)
3-Hydroxy-3-methyl glutaryl-CoA (HMG-CoA)
HMG-CoA Lyase
(Liver mitochondria)
CH3- CO ~ S – CoA
Acetyl-CoA
CH3- CO ~ CH2 - COOH
Acetoacetate
Spontaneous NADH,H+
(Lungs & Kidneys) 3- hydroxybutyrate
Dehydrogenase
CO2
NAD+
OH
CH3- CO - CH3 CH3- CH - CH2 - COOH
Acetone 3- Hydroxybutyrate
(Expired air & Urine)
(-Hydroxybutyrate)

Regulation of Ketogenesis
Ketogenesis increases in conditions associated with:
1) Increase in the supply of free fatty acids to the liver(increased rate
of lipolysis).
2) Stimulation of fatty acid oxidation which leads to increased
production of acetyl-CoA (the building unit of ketone bodies).
3) Inhibitionof utilization of acetyl-CoA byTCA cycle.
 Regulation of ketogenesis

Triacylglycerol

1 Lipolysis

FFA

Adipose tissue

FFA
Blood

AcylCoA
Liver

2 Β-oxidation

AcetylCoA

Citric acid
3 Ketogenesis
cycle

CO2 Ketone bodies

These conditions are characterizedbyincrease ofanti-

insulin/insulin ratio, as in cases of starvation and severe
uncontrolled diabetes mellitus where:
1) There is increase in lipolysis, releasing excess free fatty acids to the
liver.
2) Fattyacyl-CoA produces inhibition of acetyl-CoA carboxylase,
decreasing malonyl-CoA. This leads to activation of CPT-1 allowing
fatty acyl-CoA to enter the mitochondria for β-oxidation.
3) B-Fatty acid oxidation leads to increase in NADH and FADH2 and
thus ATP. These lead to inhibition of glycolysis and TCA cycle. The
decrease in glucose oxidation and stimulation of gluconeogenesis lead
to decrease availability of oxaloacetate, for citrate synthase of TCA
cycle and thus acetyl-CoA is diverted towards ketogenesis.
4) High NADH/NAD ratio results in conversion of oxaloacetate to
malate which is transported to cytosol for gluconeogenesis.

Ketolysis
Definition:It is the complete oxidation of ketone bodies
Site:in the mitochondria of extrahepatic tissue. This is due to the high
activity of thiophorase(succinyl-CoA:acetoacetate CoA transferase)
in the extrahepatic tissue and its deficiency in the liver.
Steps: (see diagram)
- β–hydroxybutyrate is converted to acetoacetate, which gives two
molecules of acetyl-CoA. Acetyl-CoAis utilized byKrebs’ cycle for
complete oxidation.
- Ketolysis is dependent on activity of citric acid cycle as succinyl-
CoA needed for the thiophorase reaction is supplied from citric acid
cycle and acetyl-CoA enters the cycle for complete oxidation.

CH3-CHOH-CH2-COOH
Steps of Ketolysis 3- hydroxybutyrate
NAD+
3- hydroxybutyrate
Dehydrogenase
Succinyl-CoA NADH,H+
CH3-CO~CH2-COOH
Acetoacetate
CoA Transferase
Mitochondria of extrahepatic tissues
Citric acid cycle
Acetoacetyl-CoA
CH3-CO~CH2-CO ~ S - CoA
Citrate Succinate
Ketothiolase
CoA-SH
Oxaloacetate

2 CH3-CO ~ S - CoA
Acetyl-CoA

Regulation of Ketolysis
- Ketolysis is determined by the availability of oxaloacetate for
oxidation in Krebs’ cycle. Thus ketolysis is stimulated by insulin.
- Insulin increases glucose uptake and its oxidation by tissues
providing oxaloacetate for complete oxidation of acetyl-CoA in
extrahepatic tissues.
- Anti-insulin hormones inhibit ketolysis by opposite effects to
insulin (inhibit glucose utilization in extrahepatic tissues).

Ketosis
- This is a condition characterized by increased ketone bodies in the
blood (ketonemia) and in the urine (ketonuria).
- Normally ketone bodies in blood range from 0.5-3mg/dL. In urine,
it is less than 15mg/day.

Causes of Ketosis
Ketosis occurs in conditions where the rate of ketogenesis exceeds the
rate of ketolysis i.e. in conditions where there is markedstimulation of
ketogenesis, as in the following:
-Starvation, low carbohydrates and high fat in diet.
-Severe uncontrolled diabetes mellitus.
-Prolonged administration of anti-insulin hormones.
-Prolonged and severe muscular exercise.
Effects of ketosis
The increased production of3-hydroxybutyrate and acetoacetate leads
to acidosisand may lead to coma and death.
N.B.: Ketogenic substances include:fatty acids, ketogenic amino
acids and anti-insulin hormones.
Anti-ketogenic substances include:carbohydrates, glucogenic amino
acids, glycerol and insulin.
 Adipose Tissue Metabolic ChangesDuring
Ketosis
TAG
Increased of Antiinsulin / Insulin
Ratio in Blood

Activation
of Lipolysis Brain
Oxidation for
energy production

Ketone
Glycerol FFA Glucose bodies

Glucose Glucose
Oxidation for
BLOOD energy production

Glycerol FFA

Ketogenesis
- Pyruvate ketolysis
- Lactate
- Oxaloacetate Ketone
Ketone Ketone
- Glucogenic bodies
bodies bodies
amino acids
Extrahepatic Tissues
Liver (muscles)
Ketogenic In Urine
Amino acids (ketonuria)