1. Ketone bodies metabolism (Ketogenesis & Ketolysis)

2. Ketogenesis & Ketolysis
Liver converts acetyl CoA produced mainly from β-oxidation of fatty acids into ketone bodies (Ketogenesis) which are transported in the blood to the peripheral tissues where they are reconverted to acetyl CoA (ketolysis) and oxidized by the TCA cycle to produce energy

3. Ketogenesis Definition:
Ketogenesis is the synthesis of ketone bodies from acetyl CoA which is derived mainly from β-oxidation of fatty acids
Types of ketone bodies:
Acetoacetate,
3–hydroxybutyrate (β-hydroxybutyrate)
Acetone
Site:
Sub-cellular site: Mitochondria
Organ (tissue) site: liver

4. Steps of ketogenesis in the liver
Fatty acid β-oxidation
LIVER
Extrahepatic tissues can not form ketone bodies due to absence of HMG CoA synthase enzyme
2 acetyl CoA
Thiolase
CoA
Acetoacetyl CoA
Acetyl CoA
HMG CoA synthase only in liver
CoA
BLOOD
β-hydroxy-β-methylglutaryl CoA (HMG CoA)
HMG CoA lyase
Acetyl CoA
Acetoacetate
spontaneous
Acetoacetate
CO2
NADH+H†
β-hydroxybutyrate dehydrogenase
Acetone
NAD†
β-hydroxybutyrate
β-hydroxybutyrate
Steps of ketogenesis in the liver

5. REGULATION OF KETOGENESIS
1. Increased free fatty acids in blood stimulates ketogenesis in the liver these free fatty acids are released from adipose tissue (i.e., increased lipolysis in starvation)
2. Glucagon stimulates ketogenesis by increasing lipolysis (in starvation)
3. Insulin inhibits ketogenesis by inhibiting lipolysis and stimulating lipogenesis (in the fed state)

6. Ketolysis Definition:
Ketolysis is the process of ketone bodies utilization to produce energy during starvation
Acetoacetate & β-hydroxybutyrate are the functional ketone bodies that undergo ketolysis
Aceton is a nonmetabolizable side product which is excreted via lungs
Site:
Sub-cellular site: Mitochondria
Organ (tissue) site: extra hepatic tissues especially muscle & brain

7. Ketolysis in extrahepatic tissues as muscle & brain
β-hydroxybutyrate
β-hydroxybutyrate dehydrogenase
NADH+H†
NAD†
Acetoacetate
Thiophorase only in extraheoatic tissues
Succinate
Succinyl CoA
Acetoacetyl CoA
2 acetyl CoA
Thiolase
CoA
Liver can not utilize ketone bodies due to absence of thiophorase enzyme
Thiophorase is also called acetoacetate: succinyl-CoA transferase

8. Metabolism of Ketone Bodies

9. Ketolysis in extrahepatic tissues e.g., muscle
Ketogenesis in liver
Ketolysis in extrahepatic tissues e.g., muscle

10. Important
Liver can not utilize ketone bodies due to absence of thiophorase enzyme (succinyl CoA-acetoacetate transferase)
Extrahepatic tissues can not form ketone bodies due to absence of HMG CoA synthase enzyme
RBCs can not utilize ketone bodies due to absence of mitochondria
Acetone does not undergo ketolysis but it is excreted through lungs

11. Excessive production of ketone bodies in diabetes mellitus
When the rate of formation of ketone bodies in the liver is greater than the rate of their utilization by the extrahepatic tissues, their levels begin to rise in the blood (ketonemia) and in the urine (ketonuria)
Ketone bodies are relatively strong acids so ketonemia causes acidemia (Ketoacidosis) This acidification of the blood is dangerous because it impairs the ability of hemoglobin to bind oxygen.

12. Excretion of excess acetone through the lungs gives the breath a characteristic fruity odor
These conditions are seen in cases of uncontrolled, type 1 (insulin-dependent) diabetes mellitus.
Normal blood level of ketone bodies is less than 3mg/dl ,but in diabetic ketoacidosis it may reach 90 mg/dl

13. In diabetic patients the events that can lead to ketosis are:
KETOACIDOSIS
In diabetic patients the events that can lead to ketosis are:
Relative or absolute (most common cause) deficiency of insulin
Mobilization of free fatty acids (from adipose tissues)
Increased delivery of free fatty acids to the liver
Increased uptake and oxidation of free fatty acids by the liver
Accelerated production of ketone bodies by the liver