Ketone body metabolism

1. Ketone Body Metabolism
Dr. Ashok Kumar J
International Medical School
Management and Science University
Malaysia
9/10/2014 Dr. Ashok Kumar J; IMS; MSU 1

2. Objectives :
• What are Ketone Bodies ?
• How they are produced and Utilized ?
• How ketone body metabolism is regulated ?
• When and why excess amount of ketone bodies are produced ?
• What is Ketosis and Ketoacidosis ?
• Biochemical basis for diabetic and starvation ketosis and ketoacidosis.
9/10/2014 Dr. Ashok Kumar J; IMS; MSU 2

3. Catabolism of fatty acids
Under certain conditions
1. When glucose is not available to the cells of
the body (starvation)
2.When glucose cannot be utilized by the cells of
the body ( Diabetes mellitus)
Fatty acids are catabolized
to provide energy
9/10/2014 Dr. Ashok Kumar J; IMS; MSU
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4. Triglyceride
Glycerol
Fatty Acids
Albumin
adipose
tissue
Fatty Acids
liver
Fatty Acids
Fatty Acids
Fatty
Acids
albumin
b-oxidation
Acetyl Co A
TCA
Cycle
Energy for the Brain and
Extrahepatic tissues
Hormone
Sensitive
Lipase
Glucagon
Epinephrine
Glucocortic-oids
+
1
3
2
mitochondria
Dr. Ashok Kumar J; IMS; MSU
Ketone
Bodies
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5. Ketone Bodies
Dr. Ashok Kumar J; IMS; MSU
High rate of Fatty Acid
Oxidation in Liver
Produce considerable
amount of
Acetoacetate,
3-hydroxybutyrate
Acetoacetate
continuously under go
decarboxylation to form
acetone
•Acetoacetate
•3 Hydroxy butyrate
•Acetone
Are called ketone bodies
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6. Ketone Body Synthesis (Ketogenesis)
O
CH 3-C
CH3-C
S-CoA O
S-CoA
Acetyl CoA Acetyl CoA
Thiolase
S-CoA
HS-CoA
9/10/2014 Dr. Ashok Kumar J; IMS; MSU 6

7. Ketone Body Synthesis (Ketogenesis)
O
CH2-C
CH3-C -
O
S-CoA
O
CH3-C
S-CoA
O
CH3-C
S-CoA
Acetoacetyl CoA
OH
Acetyl CoA
CH3-C -
O
CH2 -C
S-CoA
O
- O
CH2-C
HMG CoA Synthase
HS-CoA
HMG CoA Lyase
O
CH3-C
O
- O -
CH2-C
acetoacetate
HMG CoA
Acetyl CoA
Dr. Ashok Kumar J; IMS; MSU 7
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8. O
CH3- CH
Acetone
Dr. Ashok Kumar J; IMS; MSU
O
CH3- C
O
- O
CH2- C
acetoacetate
NAD+
NADH + H+
OH
-CH3
CH3- CH
O
- O
-CH2- C
3-Hydroxy butyrate
CO2
Ketone Bodies
3-Hydroxy butyrate
Dehydrogenase
8
Ketone Body Synthesis (Ketogenesis) continued……..
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9. Ketone Bodies
• The ratio of [3 Hydroxybutyrate] / [Acetoacetate] in
blood varies from 1:1 to 10:1
• Acetone is volatile – Expelled out through Lungs
• Acetoacetate and 3 Hydroxybutyrate are excreted
through urine
Dr. Ashok Kumar J; IMS; MSU 9
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10. Ketone bodies are produced in Liver
Liver is not able to utilize ketone bodies due to
the absence of the enzyme required to activate
acetoacetate
Extrahepatic tissues contain the enzyme
required to activate acetoacetate (They are able
to utilize ketone bodies)
9/10/2014 Dr. Ashok Kumar J; IMS; MSU
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11. Utilization of ketone bodies
3-Hydroxy butyrate
Dehydrogenase
S-CoA 2
Dr. Ashok Kumar J; IMS; MSU
OH
CH3- CH
O
- O
-CH2- C
3-Hydroxy butyrate
NADH + H
NAD+
O
CH3- C
O
- O
CH2- C
acetoacetate
O
O
CH3- C
O
CH2- C
S-CoA
Acetoacetyl CoA
Succinyl CoA –
acetoacetate CoA
transferase
( Thiophorase)
CH3-C
CoA-SH
Thiolase
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12. Acetyl CoA enters TCA cycle - Oxidized further to derive energy
After about 3 days of starving liver forms lot of ketone bodies
• Brain fulfils 1/3 of its energy needs from Acetoacetate.
• Heart also uses Ketone bodies
After several weeks of starvation ketone bodies become major
fuel of brain (brain derives 60-75% of energy from ketone bodies
under conditions of prolonged starvation)
Now only 40gm glucose / day is needed by brain
compared to 120 gm/day on 1st day of starvation
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13. Regulation
The liver extracts about 30% of the free
fatty acids passing through it
The factors regulating mobilization of free fatty acids
from adipose tissue are important in controlling oxidation of fatty
acids
Increased Mobilization of fatty acid
Increased Ketogenesis
Dr. Ashok Kumar J; IMS; MSU
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Regulated at three crucial steps
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14. [INSULIN] /
[GLUCAGON]
Glucose
CPT - I _
CPT-I (CAT –I) gateway into the mitochondria
Triglycerol
Fatty Acid
Malonyl CoA
AcetylCoA
Carboxylase
Citrate
Oxaloacetate
Pyruvate
Oxaloacetate
Acetyl CoA
Pyruvate
Citrate
Dr. Ashok Kumar J; IMS; MSU
[INSULIN] /
[GLUCAGON] 2
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15. Increase in [NADH] /[NAD] ratio
Affect the equilibrium between
Fall in the concentration of Oxaloacetate particularly
with in the mitochondria
Impair the ability of TCA cycle to use acetyl CoA
Divert it towards ketogenesis
Dr. Ashok Kumar J; IMS; MSU
malate and oxaloacetate
15
3 Regulation
Oxaloacetate Is diverted
for Gluconeogenesis
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16. Ketosis &
Ketoacidosis
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17. Ketonemia; Ketonuria
• The concentration of total ketone bodies in blood of well
fed mammals does not exceed 0.2mmol/L
• Loss via urine is usually less than 1 mg/24h in humans
• Blood level of ketone bodies increased – Ketonemia
• Excretion of ketone bodies in urine increased - Ketonuria
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18. Ketosis ; Ketoacidosis
Ketonemia + Ketonuria = Ketosis
Ketone bodies (acetoacetic acid & 3-OH Butyric acid ) are
acidic in nature
Hydrogen ions are neutralized by bicarbonate (HCO3
-) level of the blood decreases –
metabolic acidosis
Dr. Ashok Kumar J; IMS; MSU
-) of
the blood
Bicarbonate (HCO3
Metabolic acidosis is due to accumulation of ketone bodies
so it is called ketoacidosis
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19. Salient Features of Ketosis …..
• Acidosis
• Kussmaul's respiration
• Smell of acetone in patient's breath.
• Osmotic diuresis induced by ketonuria may lead to dehydration
• Sodium loss (The ketone bodies are excreted in urine as their sodium salt)
• Dehydration
• Coma
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20. Ketoacidosis
seen when there is excess fatty acid oxidation by the liver
Excess fatty acid oxidation by the liver – when there is excess
mobilization of the fatty acids from adipose tissue
Excess mobilization of fat from adipose tissue
when (Insulin : Glucagon)
1. Uncontrolled Diabetes Mellitus:
Diabetic ketoacidosis
2. Prolonged Starvation:
Starvation Ketoacidosis
9/10/2014 Dr. Ashok Kumar J; IMS; MSU
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21. Diabetic Ketoacidosis
Relative or absolute deficiency of insulin combined with
counter regulatory hormone excess
[INSULIN] / [GLUCAGON]
Excess mobilization of fatty acids
Hyperglucagonemia alters hepatic metabolism to
favor ketone body formation, through activation of the
enzyme carnitine palmitoyltransferase I.
Excess b-oxidation of fatty acids in the hepatocytes
Excess ketone body formation
9/10/2014 Dr. Ashok Kumar J; IMS; MSU
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22. Starvation Ketoacidosis
Blood glucose level is decreased
[INSULIN] / [GLUCAGON]
Excess mobilization of fatty acids
Hyperglucagonemia alters hepatic metabolism to
favour ketone body formation, through activation of the
enzyme carnitine palmitoyltransferase I.
Excess b-oxidation of fatty acids in the hepatocytes
Excess ketone body formation
9/10/2014 Dr. Ashok Kumar J; IMS; MSU
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23. Test for Ketone bodies
Rothera’s test :
• Urine taken in a test tube
• Saturated with ammonium sulphate
• drops of freshly prepared sodium nitroprusside is added and
mixed
• Liquor ammonia through the sides of the test tube
• Appearance of a purple ring at the junction indicates presence
of ketone bodies
Gerhadt's test for acetoacetic acid:
To 5 ml of urine, add dilute ferric chloride solution drop by drop
A red color indicates the presence of acetoacetic acid
Not a sensitive test Salicylates will give a false positive test
9/10/2014 Dr. Ashok Kumar J; IMS; MSU 23

24. Management of Ketoacidosis
• Treatment is to give insulin and glucose
When glucose and insulin are given intravenously, potassium is
trapped within the cells
Fatal hypokalemia can occur
Clinician should always monitor the electrolytes
• Administration of bicarbonate, and maintenance of electrolyte and
fluid balance
9/10/2014 Dr. Ashok Kumar J; IMS; MSU 24

25. Thank You
Any questions………….. ?
drashokkumarj@gmail.com
9/S10M/201S4 - 0183246771 Dr. Ashok Kumar J; IMS; MSU 25