Metabolism of ketone bodies

1. Metabolism of ketone bodies
BEBIN LENUS
DARSH ANOOP SINGH SANDHU
DEVANSH DEEP SINGH VIRDI
GURDEEP SINGH
GURPARTAP SINGH
IKNOOR SINGH MANN

2. • Carbohydrates are essential for the metabolism
of fat or FAT is burned under the fire of
carbohydrates.
• Acetyl CoA formed from fatty acids can enter &
get oxidized in TCA cycle only when
carbohydrates are available.
• During starvation & diabetes mellitus, acetyl CoA
takes the alternate route of formation of ketone
bodies.

3. • Acetone, acetoacetate & β-hydroxybutyrate (or 3-
hydroxybutyrate) are known as ketone bodies
• β-hydroxybutyrate does not possess a keto (C=O)
group.
• Acetone & acetoacetate are true ketone bodies.
• Ketone bodies are water-soluble & energy yielding.
• Acetone, it cannot be metabolized

4. CH3 – C – CH3
O
Acetone
CH3 – C – CH2 – COO-
O
Acetoacetate
CH3 – CH – CH2 – COO-
OH
I
β-Hydroxybutyrate

5. • Acetoacetate is the primary ketone body.
• β-hydroxybutyrate & acetone are secondary ketone
bodies.
• Site:
• Synthesized exclusively by the liver mitochondria.
• The enzymes are located in mitochondrial matrix.
• Precursor:
• Acetyl CoA, formed by oxidation of fatty acids, pyruvate
or some amino acids

6. • Ketone body biosynthesis occurs in 5 steps as
follows.
1.Condensation:
• Two molecules of acetyl CoA are condensed to
form acetoacetyl CoA.
• This reaction is catalyzed by thiolase, an enzyme
involved in the final step of β-oxidation.

7. • Acetoacetate synthesis is appropriately regarded
as the reversal of thiolase reaction of fatty acid
oxidation.
2.Production of HMG CoA:
• Acetoacetyl CoA combines with another
molecule of acetyl CoA to produce β-hydroxy β-
methyl glutaryl CoA (HMC CoA).
• This reaction is catalyzed by the enzyme HMG
CoA synthase.

8. • Mitochondrial HMG CoA is used for ketogenesis.
• Cytosolic fraction is used for cholesterol
synthesis.
• HMG CoA synthase, regulates the synthesis of
ketone bodies.
3.Lysis:
• HMG CoA is lysed to form acetoacetate & acetyl
CoA.

9. • Acetoacetate may also be formed by the
degradation of carbon skeleton of ketogenic
amino acids like leucine, lysine, phenyl alanine &
tyrosine.
• HMG CoA lyase is present only in liver.
4.Reduction:
• β-hydroxybutyrate is formed by the reduction of
acetoacetate.

10. • Ratio between acetoacetate & β-hydroxybutyrate
is decided by cellular NAD:NADH ratio.
5.Spontaneous decarboxylation:
• Acetoacetate can undergo spontaneous
decarboxylation to form acetone.

12. • Ketone bodies are formed in the liver, but utilized by
the extrahepatic tissues.
• Ketone body utilisation is more pronounced when
glucose is not available as fuel source.
• Heart muscle & renal cortex also utilizes ketone
bodies as fuel, if glucose is not available, during
prolonged starvation upto 75% of enery need of the
brain are made through ketone bodies.

14. Liver
Blood Extrahepatic tissues
Acetyl CoA
Ketone bodies Ketone bodies Ketone bodies
FFA Acetyl CoA
TCA cycle
Acetone in
breath
Ketone
bodies in urine

15. • The rate of synthesis of ketone bodies by the
liver is such that they can be easily metabolized
by extrahepatic tissues.
• Blood level of ketone bodies is <1 mg/dl.
• Ketonemia:
• When the rate of synthesis of ketone bodies
exceeds the rate of utilization, their concentration
in blood increases - ketonemia.

16. • Ketonuria:
• The term ketonuria represents the excretion of
ketone bodies in urine
• Ketonemia, ketonuria & smell of acetone in
breath.
• All these three together known as ketosis.

17. • Diabetes mellitus:
• Untreated DM is the most common cause.
• DM is associated with insulin deficiency, causes
the accelerated lipolysis & more fatty acids are
released into circulation.
• Oxidation of these FA increases Acetyl CoA.

18. • Enhanced gluconeogenesis restricts the
oxidation of acetyl CoA by TCA cycle.
• Since availability of oxaloacetate is less.
• Finally, acetyl CoA is diverted for ketone bodies
synthesis in DM.

19. • In starvation, the dietary supply of glucose is
decreased in starvation.
• Starvation is accompanied by increased
degradation of fatty acids.
• During prolonged starvation, ketone bodies are
the major fuel source for the brain & other parts
of central nervous system.

20. • Available oxaloacetate is channeled to
gluconeogenesis.
• Increased rate of lipolysis is to provide alternate
source of fuel.
• The excess acetyl CoA is converted to ketone
bodies.
• The high glucagon favors ketogenesis.
• The brain derives 75% of energy from ketone
bodies under conditions of fasting.

21. • Hypermesis (vomiting) in early pregnancy may also lead
to starvation-like condition & may lead to ketosis.
• During starvation & DM, level of glucagon is increased.
• Glucagon inhibits glycolysis, activates gluconeogenesis &
lipolysis, decreases malonyl CoA level & stimulates
ketogenesis.

22. Diagnosis of ketosis
• Rother’s test : Detection of ketone bodies in
urine.
• Supportive evidences : serum electrolytes,
acid-base parameters, glucose and urea
estimation.
• Differential diagnosis : Diabetic ketoacidosis
patient will give positive benedict’s test as
well as rothera’s test. But in starvation ketosis
benedict’s test is negative but rother’s test is
positive.

23. Management of ketoacidosis
• Treatment is to give insulin and glucose.
• Administration of bicarbonate, and
maintenance of electrolyte and fluid balance
are very important aspects.

24. Fatty liver (Steatosis)
Definition:
• It is the excess depositon of fat in liver
beyond its capacity to transport or
utilize
Basically speaking:
• FUNCTION OF LIVER: Lipids are
synthesised by the liver and are
either—transported or utilized through
ketolysis

25. Causes of Fatty liver
1) Excess fat intake from the diet: beyond the limit of
liver to metabolise. Excess cholesterol competes with
the phospholipids for ESSENTIAL FATTY ACIDS and
thus apoproteins not formed by the body.
2) Chronic alcoholism: Oxidation of alcohol– form
NADH– causes less formation of oxaloacetate from
malate(KREB).. FA are utilised via Acetyl COA thus
leads to excess accumilation in liver

26. CAUSES OF FATTY LIVER
3)PEM : It is deficiency of protein–
deficiency of amino acids– which are
required for apo-protein synthesis. Synthesis
of phospholipids impaired due to excess
dietary cholesterol intake– which competes
with it for essential FA
4)Chemical Factors : CCL4, Pb, inhibits
protein biosynthesis– less symthesis of apo-
proteins – accumulation FA.

27. Consequences Of FL
Cirrhosis of liver: excess fat depositon
depositonof the liver cells andlysiscauses
tissuefibrousof.
High fat intakencreased TAG synthesis:I
cause increased TAG(storage form); excess
carbohydrate also made to fats
Diabetes Mellitus and starvation: Less
utilisation of carbohydrates due to excess fat
in body; accumilates FFA in liver.

28. LIPOTROPIC FACTORS
Definition:
These are factors which facilitate transport of TAG
from liver to be utilized by the tissues and thus
prevent lipid accumilation. EXAMPLES:
1. Choline and Inositol : part of phospho lipids and thus
part of lipo-proteins.
2. Methyl group : needed for carnitine synthesis for
transport of FA across inner mytochondrial membrane
during fatty acid oxidation.
3. Vit-E ; Se; omega-3- fatty acid : anti oxidant effect.

29. Antilipotropic Factors
Definition:
These are substances which inhibit mobilization
of fats from the liver.
Causes:
1. Substances Which inhibit phospholipid
biosynthesis.
2. Substances Which inhibit protein biosynthesis.