Ketone bodies

1. Ketone bodies Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies which are: 1- Acetoacetic acid 2- β-hydroxy butyric acid 3- Acetone Functions of ketone bodies: 1-Used as source of energy. They are reconverted into acetyl CoA which is oxidized in Kreb's cycle to give energy. 2- In prolonged fasting and starvation, ketone bodies can be used as source of energy by most tissues except liver. N.B. In fasting, most tissues get energy from oxidation of both ketone bodies and fatty acids, but the brain gets its energy from oxidation of ketone bodies. Brain never oxidizes fatty acids.

2. Synthesis of ketone bodies by the liver (Ketogenesis) Site of ketogenesis:Mitochondria of livercells due to high activity of HMG-CoAsynthase, HMG- CoA- lyase. Stepsof ketogenesis:See Figure Notes on ketogenesis: 1- HMG-CoA is also a precursor of cholesterol (see latter) 2- HMG- CoAsynthase is the rate limiting enzyme in the synthesis of ketone bodies and is present in significant amounts only in the liver. 3- Acetone is a volatile, nonmetabolized product that can be released in the breath. Regulation of ketogenesis: Regulation of HMG-CoAsynthase A- Inhibited after CHO diet (after meal): CHO diet inhibits HMG-CoAsynthase. In addition, after meal, insulin is released and inhibits HMG-CoAsynthase B- Simulated in fasting & starvation, low CHO diet, and in severe (uncontrolled) DM (insulin decrease): all these factors stimulate HMG-CoAsynthase

3. HMG CoA → to extrahepatic tissues

4. Ketolysis (Use of Ketone bodies by peripheral tissues) Def. It is the complete oxidation (breakdown) of ketone bodies (β- hydroxybutyrate) into energy + CO2 + H2O Site: Mitochondria of the extrahepatic tissues. Oxidation not occurs in liver due to the absence of thiophorase in the liver. Ketolysis also not occur in RBCs due to lack of mitochondria. Briefly, ketolysis occur as follow: β- hydroxybutyrate ↔ Acetoacetate (the last reversible step in ketogenesis) Acetoacetate + CoA→acetoacetylCoA → 2 Acetyl CoA→Kreb’s The conversion of Acetoacetate into AcetoacetylCoAis catalyzed by the enzyme Thiophorasewhich is present sufficiently in extra-hepatic tissues including brain. In contrast, the liver does not contain thiophorase, and therefore can’t oxidize ketone bodies or use them as a fuel.

5. Ketolysis (oxidation of ketonbodies) in extrahepatic tissues Thiophorase This enzyme is absent in liver

6. Ketosis Ketone bodies formed in the liver must be passed to blood to be oxidized. Normal blood ketone bodies must not exceed 1.5-2 mg%. Ketosis: is the increase of blood ketone bodies above normal levels. It occurs if the rate of ketogenesis increases and exceeds the rate of ketolysis. The excess ketone bodies pass to urine (ketonuria). Both acetoacetate and beta-hydroxybutyrate are acidic, and, if levels of these ketone bodies are too high, the pH of the blood drops, resulting in ketoacidosis. In severe cases of ketosis as in uncontrolled D.M. coma may be developed and the condition may be fatal. Causes of ketonemia and ketosis: 1- Severe (uncontrolled) diabetes mellitus: due to i- There is insulin deficiency, which leads to decrease in glucose oxidation, thus the body is forced to use depot fat as the main source of energy. ii- Lipolysis is stimulated, so acetyl CoA is produced in large amounts. Excess acetyl CoA condenses to give more ketone bodies.

7. 2- Starvation, low CHO and protein diet: Ketogenesis is stimulated during fast (starvation), low carbohydrate or protein diet, where the body is forced to use depot fat and ketone bodies as source of energy. So excess acetyl CoA is produced and enter in ketone bodies synthesis