KETONE BODY METABOLISM

1. Yıldırım Beyazıt University Medical Faculty Biochemistry Department KETONE BODY METABOLISM Prof. Dr. Fatma Meriç YILMAZ fatmamericyilmaz@hotmail.com

2. KetoneBodies • Ketone bodies are produced in the liver when the amount of Acetyl CoAs exceed the oxidative capacity of the liver • They are an alternative and important energy source for peripheral tissues • They are soluble in aqueous solutions and can be directly transported to the tissues with bloodstream • Extrahepatic tissues like muscle, kidney and even brain can use ketone bodies as an energy source

3. Energy for the Brain and Nerves Epinephrine Glucagon HSL ketogenesis Albumin b-oxidation Processing Overview TAG Ketone Bodies FA adipose tissue liver

4. Formation of Ketone Bodies • What are ketone bodies and under what conditions are they formed? • acetoacetate, -hydroxybutyrate, acetone • when fats are rapidly broken down

5. Usage of glycogenstores Fasting Fattyacidbreakdownfromfatcells ProlongedfastingorDiabetes Convertion of excessAcetylCoAstoketonebodies

6. O α H e- e- e- e- H β H O H α H NADH FADH2 CoA β H CoA Beta Oxidation converts fatty acids into several molecules of Acetyl CoA

7. Acety CoAs produced during fatty acid oxidation have to enter to the TCA cycle for ATP production

8. Formation of Ketone Bodies The entry of acetyl CoA into the citric acid cycle depends on the availability of oxaloacetate. The concentration of oxaloacetate is lowered if carbohydrate is unavailable (starvation) or improperly utilized (diabetes)

9. Formation of Ketone Bodies • Oxaloacetate is normally formed from pyruvate by pyruvate carboxylase (anaplerotic reaction). • However in prolonged fasting or in DM, pyruvate is not produced or the production is decreased • Insulin is decreased, glucagon is increased and this situation forces oxaloacetate to enter gluconeogenesis to produce glucose

10. Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA TCA KETONE BODY FORMATION

11. Formation of Ketone Bodies • How can ketone bodies be used? • major fuel source for heart muscle and kidney cortex • during starvation or diabetes may be used by brain • high levels of acetoacetate decreases lipolysis

12. Synthesisof Ketone Bodies Two molecules of acetyl CoA condense to form acetoacetyl CoA. Enzyme – thiolase.

13. Acetoacetyl CoA reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA. Enzyme: HMG-CoA synthase

14. 3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate. Enzyme: HMG-CoA lyase.

15. β-Hydroxybutyrate is formed by the reduction of acetoacetate by β -hydroxybutyrate dehydrogenase. • Acetoacetate also undergoes a slow, spontaneous decarboxylation to acetone. • The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate in the blood.

16. Ketone bodies are a major fuel in some tissues Ketone bodies diffuse from the liver mitochondria into the blood and are transported to peripheral tissues. Ketone bodies are important molecules in energy metabolism. Heart muscle and the renal cortex use acetoacetate in preference to glucose in physiological conditions. The brain adapts to the utilization of acetoacetate during starvation and diabetes.

17. 3-hydroxybutyrate dehydrogenase β-Hydroxybutyrate is oxidized to produce acetoacetate as well as NADH for use in oxidative phosphorylation.

18. Acetoacetate is activated by the transfer of CoA from succinyl CoA in a reaction catalyzed by a specific CoA transferase(Thiophorase). Acetoacetyl CoA is cleaved by thiolase to yield two molecules of acetyl CoA (enter the citric acid cycle).

19. Liver does not contain CoA transferase (thiophorase) Therefore, liver can notuse ketone bodies as an energy source

20. b-oxidation TCA AA CoA thiolase AACoAT Suc HMG CoA synthase SCoA 3KACoAT HMG CoA lyase 3HBDH 3HBDH AA 3HB Acetone neuron mitochondrion Ketogenesis Ketone Body Utilization TAG Generates lots of ATP hepatocyte mitochondrion Acetyl CoA Acetyl CoA AACoA AACoA HMGCoA AA 3HB

21. KETONE BODIES ARE ALTERNATIVE ENERGY SOURCES AND ARE USEFUL… BUT…… EXCESSIVE PRODUCTION OF KETONE BODIES IS HARMFUL

22. THE KETONE BODIES: FROM PROVIDERS OF ENERGY FOR LIFE TO FATAL KILLERS • When the rate of formation of ketone bodies is greater than their use their levels begin to rise in the blood (ketonemia) and in the urine (ketonuria) • Carboxyl group of a ketone body has a pKa of about 4. • Each ketone body loses a proton as it circulates in the blood and lowers the pH of the blood • Excretion of glucose and ketone bodies in the urine increases the urine volume and causes dehydration. • Increased number of H+ in a decreased volume of plasma, can cause severe acidosis called ketoacidosis

23. DIABETIC KETOACIDOSIS The absence of insulin in diabetes mellitus tissues cannot absorb glucose inhibition of glycolysis activation of gluconeogenesis activation of fatty acid mobilization by adipose tissue decrease of oxaloacetate large amounts of acetyl CoA which can not be utilized in Krebs cycle large amounts of ketone bodies (moderately strong acids) severe acidosis (ketosis) Impairment of the tissue function, most importantly in the central nervous system

24. DIABETIC KETOACIDOSIS • DKA is a medical emergency, and without treatment it can lead to death. • DKA was first described in 1886; until the introduction of insulin therapy in the 1920s it was almost universally fatal. • It now carries a mortality of less than 1% with adequate and timely treatment • It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances.

26. DIABETIC KETOACIDOSIS • DKA may be the first symptom of previously undiagnosed diabetes, but it may also occur in people known to have diabetes as a result of a variety of causes, such as intercurrent illness or poor compliance with insulin therapy • DKA is diagnosed with blood and urine tests; it is distinguished from other, rarer forms of ketoacidosisby the presence of high blood sugar levels. • Treatment involves intravenous fluids to correct dehydration, insulin to suppress the production of ketone bodies, treatment for any underlying causes such as infections, and close observation to prevent and identify complications.