Formation and utilization of ketone bodies; ketoacidosis

Formation and utilization of ketone bodies; ketoacidosis

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  By- JINAL TANDEL Assistant Professor IICP
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  Ketone bodies • Thecompounds namely acetone, acetoacetate and B- hydroxybutyrate (or 3-hydroxybutyrate) are known as ketone bodies 6/1/2021 JINAL TANDEL 2
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  Ketogenesis • The synthesisof ketone bodies occurs in the Iiver. • The enzymes for ketone body synthesis are located in the mitochondrial matrix. • Acetyl CoA, formed by oxidation of fatty acids, pyruvate or some amino acids, is the precursor for ketone bodies. 6/1/2021 JINAL TANDEL 3
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  • Ketogenesios occursthrough the following reaction: 1. Two moles of acetyl CoA condense to form acetoacetyl CoA. This reaction is catalysed by thiolase, an enzyme involved in the final step of - oxidation. 6/1/2021 JINAL TANDEL 4
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  2. Acetoacetyl CoAcombines with another molecule of acetyl CoA to produce  -hydroxy  -methyl glutaryl CoA (HMG CoA). HMG CoA synthase, catalysing this reaction, regulates the synthesis of ketone bodies. 6/1/2021 JINAL TANDEL 5
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  3. HMG CoAlyase cleaves HMG CoA to produce acetoacetate and acetyl CoA. 4. Acetoacetate can undergo spontaneous decarboxylation to form acetone. 5. Acetoacetate can be reduced by a dehydrogenease to - hydroxybutyrate. 6/1/2021 JINAL TANDEL 6
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  6/1/2021 JINAL TANDEL7
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  Utillzation of ketonebodies • The ketone bodies, being water-soluble, are easily transported from the liver to various tissues. • The two ketone bodies-acetoacetate and -hydroxybutyrate serve as important sources of energy for the peripheral tissues such as skeletal muscle, cardiac muscle/ renal cortex etc. • During prolonged starvation, ketone bodies are the major fuel source for the brain and other parts of central nervous system. • It should be noted that the ability of the brain to utilize fatty acids for energy is very limited. 6/1/2021 JINAL TANDEL 8
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  • Reactions ofketone bodies: • -Hydroxybrutyrate is first converted to acetoacetate (reversal of synthesis) an metabolized. • Acetoacetate is activated to acetoacetyl CoA by a mitochondrial enzyme thiophorase (succinyl CoA acetoacetate CoA transferase). • The coenzyme A is donated by succinyl CoA, an intermediate in citric acid cycle. • Thiophorase is absent in liver, hence ketone bodies are not utilized by the liver. • Thiolase cleaves acetoacetyl CoA to two moles of acetyl CoA 6/1/2021 JINAL TANDEL 9
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  Metabolism (utilization) ofketone bodies to acetyl CoA 6/1/2021 JINAL TANDEL 10
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  The summary ofketone body synthesis, utilization and excretion 6/1/2021 JINAL TANDEL 11
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  Overproduction of Ketonebodies •When the rate of synthesis of ketone bodies exceeds the rate of utilization, their concentration in blood increases, this is known as ketonemia. • Ketonemia is predominantly due to incresed production of ketone bodies rather than the deficiency in their utilization. • The term ketonuria represents the excretion of ketone bodies in urine. The overall picture of ketonemia and ketonuria is commonly referred to as ketosis. • Ketosis is most commonly associated with starvation and severe uncontrolled diabetes mellitus. 6/1/2021 JINAL TANDEL 12
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  • Starvation: Starvationis accompanied by increased degradation of fatty acids to meet the energy needs of the body. This causes an over production of acetyl CoA which cannot be fully handled by citric acid cycle. • Diabetes mellitus : Diabetes mellitus is associated with insulin deficiency. This results in impaired carbohydrate metabolism and increased lipolysis, both of them ultimately leading to the accumulation of acetyl CoA and its conversion to ketone bodies 6/1/2021 JINAL TANDEL 13
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  Ketoacidosis • Both acetoacetateand -hydroxybutyrate are strong acids. Increase in their concentration in blood would cause acidosis. • The carboxyl group has a pKa around 4. Therefore, the ketone bodies in the blood dissociate and release H+ ions which lower the pH. • Further, the volume of plasma in the body is reduced due to dehydration caused by the excretion of glucose and ketone bodies. • Diabetic ketoacidosis is dangerous-may result in coma, and even death, if not treated. Ketosis due to starvation is not usually accompanied by ketoacidosis. 6/1/2021 JINAL TANDEL 14
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  • Treatment ofketoacidosis: Administration of insulin is necessary to stimulate uptake of glucose by tissues and inhibition of ketogenesis 6/1/2021 JINAL TANDEL 15