KETONE BODY METABOLISM

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KETONE BODY METABOLISM
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• Dr.Siddiqui Abdulmoeed
• Associate Professor of Biochemistry
• College of Medicine
• Al-jouf University

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OBJECTIVES

• Define ketone bodies. List the functions of
  ketone bodies
• Describe the synthesis of ketone bodies
  (Ketogenesis)
• Describe the catabolism of ketone bodies
  (ketogenolysis)
• Define Ketoacidosis, list its main metabolic
  causes explain its mechanism of occurrence.

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Define ketone bodies.

• KETONE BODIES KBs are water soluble organic
  compounds generated in human body under certain
  metabolic conditions. The compounds acetone,
  acetoacetate and ßhydroxy butyrate are known as
  ketone bodies.

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Importance and functions

• Ketone bodies being water soluble are easily
  transported from liver to various tissues.
• The two ketone bodies acetoacetate and ßhydroxy
  butyrate serve as important sources of energy
  for peripheral tissues like skeletal muscle,
  cardiac muscle, renal cortex etc.

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Importance ad functions-contd

• The production and utilization of KBs becomes
  more significant when glucose is in short supply
  to tissues as observed in starvation and diabetes
  mellitus
• During prolonged starvation KBs are the major
  source of fuel for brain and other parts of
  Central Nervous System.
• RBCs lack mitochondria, hence cannot utilize KBs.

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Synthesis of Ketone bodies- ketogenesis

• Site of Ketogenesis
• It occurs in liver and the enzymes responsible
  for it are located in mitochondrial matrix
• Steps
• Formation of Acetoacetyl CoA. Enzyme involved is
  ß-Thiolase.
• Formation of HMG-CoA. Enzyme involved is HMG Co A
  Synthase which also regulates KB synthesis.
• Breakdown of HMG-CoA to acetoacetate and acetyl
  CoA by HMG-CoA lyase.
• spontaneous breakdown of Acetoacetate to Acetone.
• Formation of ß-hydroxy butyrate by enzyme
  ßhydroxy butyrate dehydrogenase

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Catabolism of ketone bodies (ketolysis)

• During prolonged starvation KBs are the major
  source of fuel for brain and other parts of
  Central Nervous System.
• This an adaptation to survive during periods of
  food deprivation.
• Liver lacks Thiophorase enzyme hence cannot
  utilize KBs
• .

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Ketone Bodies As Energy Sources
In liver
?-Hydroxybutyrate Acetoacetate
Succinyl CoA
Acetoacetate is major energy source in cardiac
muscle and renal cortex also in brain
in starvation and diabetes
Thiophores
Not found in liver
Thiolase
Succinate
Acetoacetyl CoA
2 Acetyl CoA
Combines with oxaloacetate
TCA Cycle
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Ketoacidosis

• In normal humans there is a constant production
  of ketone bodies by liver and their utilization
  by extra hepatic tissues.
• The blood level of KBs is about 1 mg/dl in a
  normal human adult. Their excretion in urine is
  very low and undetectable by routine tests.
• When the rate of synthesis of ketone bodies
  exceeds the rate of utilization , their level
  increases in blood. This is known as ketonemia.
• Ketonemia is produced due to increased production
  rather than decreased utilization.

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• In ketinemia , the excretion of KBs increases in
  urine, this is known as ketonuria.
• The overall picture of ketnemia and ketonuraia is
  called as Ketosis.
• Both acetoacetate and ßhydroxy butyrate are
  strong acids. They dissociate in blood and
  release H ions, which lowers the pH. This
  decrease in blood pH as a result of severe
  ketosis is called as Ketoacidosis.

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Metabolic causes of Ketoacidosis

• Starvation
• In starvation the fatty acids and amino acids
  are used for energy needs of the body after the
  glucose reserves are finished.
• This results in overproduction of Acetyl CoA
  which is not fully handled by TCA cycle .
• TCA cycle is impaired due to deficiency of
  oxaloacetate which is diverted to
  gluconeogenesis.
• The final result is overproduction of KBs from
  acetyl CoA.

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• Diabetes Mellitus
• Uncontrolled DM is associated with impaired
  carbohydrate metabolism and increased lipolysis,
  both of which lead to accumulation of Acetyl CoA
  and its ultimate conversion to KBs.
• In severe Diabetes the KB levels in blood may
  reach as high as 100 mg /dl and urinary excretion
  may be as high as 500 mg/day.

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• In diabetes loss of glucose and water in urine
  leads to decrease in blood volume and further
  complicate the condition.
• Diabetic Ketoacidosis is dangerous and may result
  in coma and death if untreated.
• Ketosis due to starvation is usually not
  accompanied by Ketoacidosis

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Thanks Best Wishes