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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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

7. 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.

8. 8  -Hydroxybutyrate Acetoacetate Succinyl CoA Succinate Acetoacetyl CoA Thiophores 2 Acetyl CoA Thiolase TCA Cycle Ketone Bodies As Energy Sources In liver Acetoacetate is major energy source in cardiac muscle and renal cortex; also in brain in starvation and diabetes Not found in liver Combines with oxaloacetate

9. 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.

10. 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.

11. 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.

12. 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.

13. –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

14. Thanks & Best Wishes