The document summarizes ketone body metabolism. It describes how ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone) are synthesized from acetyl-CoA in the liver during periods of low carbohydrate availability, such as fasting or uncontrolled diabetes. Ketone bodies can be used as an energy source by extrahepatic tissues and are produced through a series of reactions catalyzed by enzymes such as acetoacetyl-CoA thiolase and HMG-CoA lyase. Regulation of ketone body production occurs through factors that influence fatty acid breakdown and acetyl-CoA production.

1. Metabolism of Ketone Bodies
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India

2. When fatty acid oxidation increases, large
amounts of acetyl CoA are produced
Acetyl CoA formed from fatty acids is
normally oxidized in Krebs cycle
When its production exceeds the capacity
of Krebs cycle, it is diverted to ketogenesis

3. The ketone bodies are:
Acetoacetate
b-Hydroxybutyrate
Acetone
Ketogenesis is synthesis of ketone bodies

4. CH3‒C‒CH2‒COOH
O
II
Acetoacetate
CH3‒C‒CH3
O
II
Acetone
CH3‒CH‒CH2‒COOH
OH
I
b-Hydroxybutyrate

5. Liver is the only organ capable of
ketogenesis
Ketogenesis occurs in the mitochondria of
liver cells
Production of acetyl CoA also occurs in
mitochondria

6. Ketone bodies are used as a source of
energy when carbohydrates are
unavailable
Carbohydrates may be physically
unavailable during prolonged fasting
They may be metabolically unavailable in
diabetes mellitus

7. Ketone bodies are synthesized from
acetyl CoA
Two molecules of acetyl CoA condense to
form acetoacetyl CoA
This reaction is catalysed by acetoacetyl
CoA thiolase
Synthesis of ketone bodies

8. II
OAcetyl CoA
Acetoacetyl
CoA thiolase
Acetoacetyl CoA
O
II
CH3‒C ~ S‒CoA
CoA ‒SH
C‒CH2‒C ~ S‒CoA
CH3
|
CH3‒C ~ S‒CoA
O
II
Acetyl CoA
O
II

9. Acetoacetyl CoA condenses with another
molecule of acetyl CoA
The product is b-hydroxy-b-methyl glutaryl
CoA (HMG CoA)
This reaction is catalyzed by HMG-CoA
synthetase

10. II
O
Acetoacetyl CoA
C‒CH2‒C ~ S‒CoA
CH3
|
HMG CoA
synthetase
CH3‒C ~ S‒CoA + H2O
CoA ‒SH
b-Hydroxy-b-methylglutaryl CoA
(HMG CoA)
O
II
O
II
HOOC‒CH2‒C‒CH2‒C ~ S‒CoA
OH
CH3 O
II

11. The reaction catalyzed by HMG CoA
synthetase is the rate-limiting reaction of
ketogenesis
Mitochondrial HMG CoA synthetase is
different from the cytosolic enzyme
involved in cholesterol synthesis

12. HMG CoA is cleaved into acetoacetate
and acetyl CoA
This reaction is catalyzed by HMG CoA
lyase
Acetoacetate is the first ketone body to
be synthesized

13. Acetoacetate
CH3‒C‒CH2‒COOH
HMG CoA
lyaseCH3‒C ~ S‒CoA
b-Hydroxy-b-methylglutaryl CoA (HMG CoA)
O
II
O
II
HOOC‒CH2‒C‒CH2‒C ~ S‒CoA
OH
CH3 O
II

14. The other two ketone bodies are formed
from acetoacetate
b-Hydroxybutyrate is formed by enzymatic
reduction of acetoacetate
Acetone is formed by spontaneous
decarboxylation of acetoacetate

15. CH3‒C‒CH2‒COOH
O
II
Acetoacetate
Spontaneous
b-Hydroxy-
butyrate
dehydrogenase
NADH + H+
NAD+
 
 CO2
CH3‒C‒CH3
O
II
Acetone
CH3‒CH‒CH2‒COOH
OH
I
b-Hydroxybutyrate

16. When fatty acids are being oxidized,
NADH/NAD+ ratio becomes high
Therefore, most of the acetoacetate is
reduced to β-hydroxybutyrate
b-Hydroxybutyrate is the most abundant
ketone body in blood

17. Ketone bodies are synthesized in liver but
cannot be oxidized in liver
The enzymes required for the utilization
of ketone bodies are not present in liver
However, ketone bodies can be used by
tissues other than liver
Oxidation of ketone bodies

18. When availability of carbohydrates is low,
liver releases ketone bodies into blood
They are taken up by extrahepatic
tissues with the help of monocarboxylate
transporter 1
Ketone bodies are used as fuel by
extrahepatic tissues

19. Acetone cannot be utilized in the body; it
is lost in exhaled air and urine
b-Hydroxybutyrate and acetoacetate can
be utilized
b-Hydroxybutyrate is first oxidized to
acetoacetate

20. CH3‒CH‒CH2‒COOH
O
II
OH
|
NADH + H+
NAD+
b-Hydroxybutyrate Acetoacetate
CH3‒C‒CH2‒COOH
b-Hydroxybutyrate
dehydrogenase

21. Acetoacetate is activated to acetoacetyl
CoA
The CoA moiety is provided by succinyl
CoA
The reaction is catalysed by succinyl
CoA:acetoacetate CoA transferase

22. O
II
Succinyl CoA:
acetoacetate
CoA transferase
Acetoacetate
CH3 —C —CH2 —C ~ S —CoA
Acetoacetyl CoA
Succinyl CoA
Succinate
CH3 —C —CH2 —COOH
CH2—C ~ S—CoA
CH2 — COOH
O
II
CH2—COOH
CH2—COOH
O
II
O
II

23. Acetoacetyl CoA is converted into two
molecules of acetyl CoA
These are oxidized in the citric acid
cycle

24. Thiolase
CoA‒SH
CH3‒C‒CH2‒C ~ S‒CoA 2 CH3‒C ~ S‒CoA
Acetyl CoA
Krebs cycle
Acetoacetyl CoA
O
II
O
II
O
II

25. Normally, the production and utilization of
ketone bodies is very low
The need for ketone bodies increases
during prolonged fasting
The need also increases in uncontrolled
diabetes mellitus

26. In early starvation, heart and muscles
start using ketone bodies as a fuel
This spares glucose for use by the brain
In late stages, brain also adapts to ketone
bodies as a source of energy
This spares glucose for use by erythro-
cytes which cannot use any other fuel

27. Regulation
Fatty
acids
Glucose
Many amino
acids
Ketone bodies are formed from acetyl
CoA
Acetyl CoA can be formed from:

28. Contribution of amino acids in the
production of acetyl CoA is just about 5%
The major sources of acetyl CoA are fatty
acids and glucose
The fate of acetyl CoA depends upon
dietary and hormonal status

29. When availability of carbohydrates is
adequate, acetyl CoA is formed from
them, and is:
Oxidized in Krebs cycle or
Used for lipogenesis

30. When availability of carbohydrates is
poor, acetyl CoA is formed from fatty
acids, and is:
Oxidized in Krebs cycle or
Used for ketogenesis
Metabolism of ketone bodies is
regulated at the level of ketogenesis

31. The rate of ketogenesis is regulated by:
Rate of lipolysis in adipose tissue
Availability of glycerol-3-phosphate in liver
Availability of oxaloacetate in liver
Rate of entry of fatty acids in mitochondria
Concentration of HMG CoA synthetase

32. Triglycerides are hydrolysed in adipose
tissue by hormone-sensitive lipase
Glucagon activates hormone-sensitive
lipase during fasting by phosphorylating it
Increased availability of fatty acids in liver
increases ketogenesis
Rate of lipolysis

33. In fed state, insulin inactivates hormone-
sensitive lipase in adipose tissue by
dephosphorylating it
This decreases the availability of fatty
acids in liver
Consequently, ketogenesis is decreased

34. Fatty acids entering the liver can have
two fates
Either they are oxidized or they are
esterified with glycerol
The fate depends upon availability of
glycerol-3-phosphate
Availability of glycerol-3-phosphate

35. If glycerol-3-phosphate is available, fatty
acids are converted into triglycerides
The main source of glycerol-3-phosphate
is glucose
Thus, glucose promotes lipogenesis and
prevents ketogenesis

36. Oxaloacetate is required for entry of
acetyl CoA in Krebs cycle
Carboxylation of pyruvate is the main
source of oxaloacetate
Pyruvate is formed mainly from glucose
(by glycolysis)
Availability of oxaloacetate

37. Poor availability of glucose decreases the
formation of pyruvate and oxaloacetate
Low availability of oxaloacetate decreases
the entry of acetyl CoA in Krebs cycle
Acetyl CoA is diverted to form ketone
bodies; the rate of ketogenesis is increased

38. HMG CoA synthetase catalyses the rate-
limiting reaction of ketogenesis
HMG CoA synthetase is regulated at the
level of transcription of its gene
Transcription of HMG CoA synthetase
gene is regulated by insulin and glucagon
HMG CoA synthetase

39. Insulin decreases the expression of HMG
CoA synthetase gene
This results in decreased ketogenesis
Glucagon increases the expression of the
gene
This results in increased ketogenesis

40. Fatty acid uptake by mitochondria is
dependent upon the carnitine system
Malonyl CoA is the inhibitor of carnitine
palmitoyl transferase I
Thus, malonyl CoA regulates the entry of
fatty acids into mitochondria
Entry of fatty acids in mitochondria

41. Malonyl CoA is formed by carboxylation of
acetyl CoA
The reaction is catalysed by acetyl CoA
carboxylase
Acetyl CoA carboxylase is subject to
phosphorylation and dephosphorylation

42. In the fed state, insulin dephosphorylates
acetyl CoA carboxylase
The enzyme becomes active and converts
acetyl CoA into malonyl CoA
Malonyl CoA inhibits transport of fatty acids
into mitochondria
This decreases the oxidation of fatty acids,
production of acetyl CoA and ketogenesis

43. In fasting state, glucagon phosphorylates
acetyl CoA carboxylase
Acetyl CoA carboxylase becomes inactive;
production of malonyl CoA decreases
Uptake of fatty acids by mitochondria is no
longer inhibited
Oxidation of fatty acids, production of
acetyl CoA and ketogenesis are increased

44. Ketosis
Ketosis is a condition in which:
Ketone bodies accumulate in the
body
Blood level of ketone bodies is
raised (hyperketonaemia)
Ketone bodies are excreted in
urine (ketonuria)

45. Ketosis occurs when:
Availability of
glucose is low
Oxidation of fatty
acids is increased
Causes of ketosis are:
Starvation Diabetes mellitus

46. In starvation:
There is
no intake of
carbohydrates
Stored
glycogen is
soon depleted
In diabetes
mellitus:
Glucose is
present in the
body
It cannot be
utilised due to
lack of insulin

47. Due to unavailability of glucose, oxidation
of fatty acids increases
As a result, production of acetyl CoA is
increased
When Krebs cycle is saturated, acetyl
CoA is diverted to ketogenesis
Ketogenesis is also favoured by a high
[glucagon] /[insulin] ratio

48. The normal level of ketone bodies in
blood is less than 2 mg/dl
When the level reaches about 12 mg/dl:
Extrahepatic oxidative machinery
for ketone bodies is saturated
Ketone bodies accumulate in
blood and are excreted in urine

49. Acetone is volatile and is exhaled in expired
air
Therefore, the breath smells of acetone in
ketosis
Fruity smell of acetone is present in urine
also

50. Ketosis can be detected from the presence
of ketone bodies in urine
Severity of ketosis can be assessed from
the concentration of ketone bodies in blood
Anion gap in plasma can also indicate the
concentration of ketone bodies in blood

51. Acetoacetate and b-hydroxybutyrate are
relatively strong acids
Their accumulation lowers the pH of the
blood
Therefore, acidosis occurs in prolonged
starvation and uncontrolled diabetes mellitus