KETONE BODY METABOLISM

Dr.Siddiqui AbdulmoeedAssociate Professor of Biochemistry

College of MedicineAl-jouf University

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.

Define ketone bodies.

KETONE BODIES [KBs] are water soluble organic compounds generated in human body under certain metabolic conditions. The compounds acetone, acetoacetate and β–hydroxy butyrate are known as ketone bodies.

Importance and functions

• Ketone bodies being water soluble are easily transported from liver to various tissues.

• The two ketone bodies acetoacetate and β–hydroxy butyrate serve as important sources of energy for peripheral tissues like skeletal muscle, cardiac muscle, renal cortex etc.

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.

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 β-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 β-hydroxy butyrate by enzyme β–hydroxy butyrate dehydrogenase

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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-Hydroxybutyrate Acetoacetate Succinyl CoA

SuccinateAcetoacetyl CoA

Thiophores

2 Acetyl CoA

Thiolase

TCA Cycle

Ketone Bodies As Energy SourcesIn liver

Acetoacetate is major energysource in cardiac muscle andrenal cortex; also in brain instarvation and diabetes

Not found in liver

Combines with oxaloacetate

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.

• 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 β–hydroxy 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.

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.

• 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.

– 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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