ketone body metabolism dr.siddiqui abdulmoeed associate professor of biochemistry college of...
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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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