L28

Metabolism of Ketone Bodies

Dr. Nelofar Khan

July 14, 2024

www.gmu.ac.ae COLLEGE OF MEDICINE

Learning objectives
The student should be able to:
1. Name the ketone bodies.
2. Describe the pathway of ketogenesis .
3. Describe the pathway for the utilization of ketone bodies as a source of
energy.
4. Explain the basis for overproduction of ketone bodies during diabetes
mellitus & starvation.
5. Explain “ketosis and ketoacidosis”.

References:
Baynes J and Dominiczak MH. Medical Biochemistry, Elsevier; 5th Edition. 2019. ISBN: 978-0-
7020-7299-4. Chapter 11, 137-146. Available on clinical key.
https://www-clinicalkey-com.gmulibrary.com/#!/content/book/3-s2.0-B978070207299400011X?index
Override=GLOBAL
 Ketogenesis
Ketone bodies are synthesized exclusively by Liver Mitochondria.

Acetyl CoA formed by oxidation of primarily fatty acids, (or pyruvate &
ketogenic amino acids) is the precursor for ketone bodies.

Occurs when there is high rate of fatty acid oxidation in liver.

Water soluble and energy yielding (except acetone).

Primary KB Secondary KB
 Overproduction of Ketone Bodies

 In normal individuals, there is a constant production (less than

0.2mM) and utilization of K.B’s.
 Excretion occurs in minute amounts.

 Significant production (3-5mM) occurs when glucose is in short

supply to the tissues and there is increased mobilization of free fatty
acids from adipose tissues.

 Starvation & uncontrolled Type 1 Diabetes mellitus.

 Ketogenesis in Liver from Acetyl CoA
• Ketogenesis is a pathway for regenerating CoA from excess acetyl-CoA.

• CoA (Coenzyme A) is present only in catalytic amounts in tissues.

• Free CoA is required to initiate and continue the cycle of β-oxidation.

• To recycle Acetyl CoA, free CoA is released and acetate group is converted to
ketone bodies.
• Pathway involves the synthesis and decomposition of Hydroxymethylglutary CoA
(HMG CoA).

• Liver is unique in its content of HMG-CoA synthase and lyase, but is deficient in
enzymes required for metabolism of K.B, which explains their export into blood.
• Upto the formation of HMG-CoA, pathway is common for ketogenesis and
cholesterol synthesis.

• Mitochondrial HMG CoA is used for ketogenesis.

• Cytosolic fraction is used for cholesterol synthesis.

• Equilibrium between 3 - Hydroxybutyrate and acetoacetate is detemined by the

NADH / NAD+ ratio. During oxidation of fatty acids, the ratio is high so 3-
hydroxybutyrate synthesis is favoured.
Utilization of Ketone Bodies
 The ketone bodies are transported from liver to various tissues where
they serve as an important source of energy.

 Tissues which lack mitochondria (e.g., erythrocytes) cannot utilize ketone

bodies.

 Heart muscles & renal cortex prefer K.B to glucose as fuel.

 Muscles during starvation: Uses FA & KB as source of energy for first two
weeks, sparing glucose for its obligatory use.

 Brain uses KB during prolonged starvation.

 Metabolism of Ketone bodies

• Β-hydroxybutyrate Acetoacetate

• Acetoacetate + Succinyl CoA

Mitochondrial enzyme Thiophorase (Succinyl CoA:

acetoacetate CoA transferase)

Acetoacetyl CoA + Succinate

Thiolase
• Acetoacetyl CoA 2 Acetyl CoA

• Thiophorase is absent in liver, hence ketone

bodies are not utilized by liver.
• Ketosis: Under the conditions of starvation and uncontrolled diabetes
mellitus, the rate of ketogenesis exceeds the rate of their utilization.

• This result in:

ketonemia
ketonuria
Smell of acetone in breath.
In Severe Diabetes Mellitus
Deficiency of insulin results in increased lipolysis.
High FA oxidation produces excessive amount of acetyl CoA, increases NADH pool which
slows the TCA cycle.
Inhibitory effect of insulin on gluconeogenesis is absent.
Excess Acetyl CoA activate pyruvate carboxylase (gluconeogenesis)
Acetyl CoA is channeled into K.B synthesis.

It leads to ketosis & ketoacidoses.

Uncontrolled production of K.B
(In blood 90mg/dL; Normal is 3mg/dL).
K.B in urine will be 5000mg/ day.
In Starvation

Increased rate of lipolysis to provide energy.

Proposed mechanism* Oxaloacetate is utilized for gluconeogenesis.

Hence the TCA cycle is impaired.

This results in an accumulation of acetyl CoA and its diversion for

overproduction of ketone bodies.

High glucagon / insulin ratio (during starvation) favours ketogenesis.

Resulting in ketosis.
Acetyl CoA activates pyruvate
Carboxylase. Hence OXA is
Utilized for gluconeogenesis
Brain and KB
Brain derives up to 75% of energy from ketone bodies under
conditions of prolonged starvation.
It cannot use fatty acid for fuel efficiently.

Hormonal Regulation
Glucagon stimulates ketogenesis and inhibits hepatic fatty acid
synthesis.
Other anti-insulin hormones like cortisol, adrenaline and GH have
stimulatory effect on ketogenesis.
Insulin inhibits the effect of glucagon.
 REGULATION OF KETOGENESIS

• During starvation & diabetes mellitus, blood level of glucagon is increased.

• Glucagon: Inhibits glycolysis

Activates gluconeogenesis & lipolysis
Decreases malonyl CoA level
Stimulates ketogenesis

• Insulin has the opposite effect: Favours glycolysis

Inhibits gluconeogenesis
Depresses lipolysis
Increases malonyl CoA level
Decreases ketogenesis

• High glucagon to insulin ratio is potentially ketogenic.

 Why ketogenesis?
• Glucose is essential for brain and RBC’s in all nutritional states.

• Liver converts extra fatty acids into K.B’s.

• K.B’s serve as energy source for the peripheral tissues sparing glucose
for obligatory uses (brain and RBC).

• During prolong starvation:

K.B’s supply 50-70% of brains energy needs.

The order of preference in muscles is

i. K.B ii. FFA iii. Glucose
 Consequences of Ketosis

In Type I Diabetes mellitus

• Ketoacidosis: Accumulation of ketone bodies results in metabolic acidosis.
Plasma HCO3- falls since it is used up for the buffering of these acids.
• Patient will have typical acidotic breathing (Kussmaul’s respiration) due to
compensatory hyperventilation.
• Smell of acetone in breath.
• Osmotic diuresis induced by ketonuria lead to dehydration.
• Ketone bodies are excreted as their Na+ or K+ salts (loss of these cations).
• Hypokalemia, dehydration and acidosis contribute for lethal effect of
ketosis (coma and even death).
 Ketosis due to starvation is NOT usually accompanied by ketoacidosis.

Diagnosis of Ketosis

Detection of ketone bodies in urine by rothera test.

Management of Keto Acidosis

· Treat by administration of glucose, HCO3- and maintain electrolyte and fluid

balance.
· Insulin is also given to diabetic patient.
 BASIC CONCEPTS

• Increased FA oxidation is a characteristic of starvation and of diabetes mellitus,

leading to ketone body production by the liver (ketosis).
• Acetyl CoA is the precursor of KB.
• Ketone bodies are acidic; excess production over long periods as in diabetes
cause ketoacidosis.
• Any state of high glucagon / insulin ratio is potentially ketogenic.
• Ketone bodies serve as a fuel for the extra hepatic tissues.
• Brain derives up to 75% of energy from ketone bodies under conditions of
prolonged starvation.
• It cannot use fatty acid for fuel efficiently.
Thank You