ketone body metabolism by dr ashok kumar j

04/13/2023 Dr. Ashok Kumar J; IMS; MSU 1

Ketone Body Metabolism

Dr. Ashok Kumar JInternational Medical School

Management and Science UniversityMalaysia


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.

04/13/2023

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

Dr. Ashok Kumar J; IMS; MSU

Catabolism of fatty acids

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04/13/2023

Triglyceride

Fatty Acids

Glycerol

Albumin

adipose tissue

Fatty Acids

liver

Fatty Acids

Fatty Acids albumin

Acetyl Co A

b-oxidation

Energy for the Brain and Extrahepatic tissues

TCA Cycle

Hormone Sensitive Lipase

GlucagonEpinephrineGlucocortic-oids

+

1

3

2Fatty Acids

mitochondria


Ketone Bodies

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04/13/2023 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

Ketone Bodies

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CH3-C

O S-CoACH3-C

O S-CoA

CH3-C -

O

CH2-C

O

S-CoAAcetoacetyl CoA

Acetyl CoA Acetyl CoA

Thiolase HS-CoA

Ketone Body Synthesis (Ketogenesis)

Dr. Ashok Kumar J; IMS; MSU 6

04/13/2023

CH3-C -

O

CH2-C

O S-CoA

CH3-C

O S-CoA

CH3-CO

S-CoA

CH3-C -

OH

CH2 -C

O S-CoA

CH2-CO- O

HMG CoA Synthase

HS-CoA

HMG CoA Lyase

CH3-C

O

CH2-CO- O -

acetoacetate

HMG CoA

Acetoacetyl CoAAcetyl CoA

Acetyl CoA


Ketone Body Synthesis (Ketogenesis)


CH3- C

O

CH2- CO- O

acetoacetate

NAD+

NADH + H+

CH3- CH

OH -CH2- C

O- O

3-Hydroxy butyrate

CH3- CH

O -CH3

Acetone

CO2

Ketone Bodies

3-Hydroxy butyrateDehydrogenase

8

Ketone Body Synthesis (Ketogenesis) continued……..

Spontaneously

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• 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


Ketone Bodies


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)

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Utilization of ketone bodies

CH3- C

O

CH2- CO- O

acetoacetate

NAD+

NADH + H+

CH3- CH

OH -CH2- C

O- O

3-Hydroxy butyrate

3-Hydroxy butyrateDehydrogenase

CH3- C

O

CH2- C

O S-CoA

Acetoacetyl CoA

Succinyl CoA – acetoacetate CoA transferase ( Thiophorase)

CH3-C

O S-CoA2

CoA-SH

Thiolase

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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


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

Regulation

1Regulated at three crucial steps

13

04/13/2023CPT-I (CAT –I) gateway into the mitochondria

[INSULIN] / [GLUCAGON]

AcylCoATriglycerol

Fatty Acid

AcylCoA AcetylCoA

Carboxylase

Citrate

Oxaloacetate

βOxidationPyruvate

Oxaloacetate

Glucose

Acetyl CoA

Malonyl CoA

Pyruvate

AcetylCoA

Citrate

CPT - I _


AcetylCoA

[INSULIN] / [GLUCAGON] 2

14


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

Increase in [NADH] /[NAD] ratioAffect the equilibrium between

malate and oxaloacetate

15

3 Regulation

Oxaloacetate Is diverted for Gluconeogenesis

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Ketosis & Ketoacidosis


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• 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


Ketonemia; Ketonuria

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Ketonemia + Ketonuria = Ketosis


Ketosis ; Ketoacidosis

Ketone bodies (acetoacetic acid & 3-OH Butyric acid ) are acidic in nature

Hydrogen ions are neutralized by bicarbonate (HCO3-) of

the blood

Bicarbonate (HCO3-) level of the blood decreases –

metabolic acidosis

Metabolic acidosis is due to accumulation of ketone bodies so it is called ketoacidosis

18


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

04/13/2023

seen when there is excess fatty acid oxidation by the liver


Ketoacidosis

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 20


Diabetic Ketoacidosis

Excess mobilization of fatty acids

Hyperglucagonemia alters hepatic metabolism tofavor ketone body formation, through activation of the

enzyme carnitine palmitoyltransferase I.

Excess b-oxidation of fatty acids in the hepatocytes

Excess ketone body formation

Relative or absolute deficiency of insulin combined with counter regulatory hormone excess


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Starvation Ketoacidosis

Excess mobilization of fatty acids

Hyperglucagonemia alters hepatic metabolism tofavour ketone body formation, through activation of the

enzyme carnitine palmitoyltransferase I.

Excess b-oxidation of fatty acids in the hepatocytes

Excess ketone body formation


Blood glucose level is decreased

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Test for Ketone bodiesRothera’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 dropA red color indicates the presence of acetoacetic acidNot a sensitive test Salicylates will give a false positive test


Management of Ketoacidosis

• Treatment is to give insulin and glucose When glucose and insulin are given intravenously, potassium is

trapped within the cellsFatal hypokalemia can occurClinician should always monitor the electrolytes

• Administration of bicarbonate, and maintenance of electrolyte and fluid balance


Thank You

Any questions………….. ?

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