Ketone Bodies, Ketogenesis, and Ketosis: A Comprehensive Guide PDF

Ketone bodies Definition: They are also called partially oxidized fatty acids. They are three in number that are produced by the liver. They include: 1. Acetoacetate "acetoacetic acid": 2. β-Hydroxybutyric acid. 3. Acetone. Functions: They are important source for energy during prolonged...

Ketone bodies Definition: They are also called partially oxidized fatty acids. They are three in number that are produced by the liver. They include: 1. Acetoacetate "acetoacetic acid": 2. β-Hydroxybutyric acid. 3. Acetone. Functions: They are important source for energy during prolongedfasting & starvation for many tissues including the brain but not for the liver as it lacks the enzymes needed for activation of ketone bodies for their oxidation "thiopherase and thiokinase".  Ketogenesis Definition: It is synthesis of ketone bodies from active acetate derived from fatty acid oxidation & ketogenic amino acids. Site: Intracellular location: Mitochondria. Organ location: Liver. Steps: The first ketone body formed is acetoacetate then the other two ketone bodies are derived from it. I) Formation of acetoacetate: A) Formation of acetoacetyl CoA: By two pathways: 1. The last four carbon atom product during the course of β- oxidation of fatty acids with even number. OR 2. By condensation of two molecules of acetyl CoA. B) Conversion of acetoacetyl CoA to acetoacetate: By simple deacylation of acetoacetyl CoA to produce acetoacetate II)Formation of β- Hydroxybutyric acid: From acetoacetate by β- Hydroxybutyric acid dehydrogenase with consumption of NADH+H. III) Formation of acetone: Acetone is lost in the expired air & urine, so in uncontrolled D.M patients their urine & breath have acetone odor.  Regulation of ketogenesis: Conditions associated with increased ketogenesis: 1. Starvation & fasting. 2. D.M. 3. High fat diet. 4. Carbohydrate poor diet. Ketogenesis is regulated by: 5. Rate of free fatty acid come to the liver. 6. Hormonal regulation. 7. Amount of energy inside the cell.  After meal: 1. In the extra-hepatic tissues: Secretion of insulin which inhibits lipolysis →↓F.F.As in the plasma & ↓hepatic uptake of free fatty acids. 2. In the liver: Inhibition of β-oxidation due to inhibition of carnitine acyl transferase-I →↓ acetyl CoA "precursor for ketone bodies" production & so decrease ketogenesis.  During starvation: – In the extra-hepatic tissues: Secretion of anti- insulin hormone "glucagon" → stimulation of lipolysis →↑F.F.As in the plasma & ↑hepatic uptake of free fatty acids. – In the liver: Stimulation of β-oxidation of fatty acids & increased production of acetyl CoA , but is it will pass to TCA cycle to be oxidized to CO2 & H2O or to ketogenesis for ketone bodies formation , this is determined by the amount of energy inside the cell. Presence of excess ATP → shift acetyl CoA into ketogenesis pathway. Presence of decreased ATP → shift acetyl CoA into oxidation in the TCA.cycle.  Ketolysis "ketone bodies oxidation Or utilization of ketone bodies" Definition: It is complete oxidation of the ketone bodies into H2O & CO2. Site: Intracellular location: Mitochondria. Organ location: Extra-hepatic tissue but never in the liver which lack enzymes needed for activation of the ketone bodies "thiophorase & thiokinase". Steps: 1 Acetone: lost in the urine & expired air as it is volatile. 2β-hydroxybutyric acid is converted into acetoacetate With the production of NADH+H  3Acetoacetic can be activated by two reactions that take place in extrahepatic tissues which activate acetoacetate to acetoacetyl CoA.  Major pathway: Thiophorase which transfers CoA from succinyl CoA to acetoacetate giving rise to acetoacetyl CoA.  Minor pathway: Activation of acetoacetate with ATP in the presence of CoA catalyzed by acetoacetyl-CoA synthetase. 4 Acetoacetyl CoA is cleaved by thiolase into two acetyl CoA molecules 5 The two acetyl CoA molecules oxidized in the TCA cycle to produce 20 ATP. Bioenergetics: Oxidation of one molecule of β- hydroxybutyric acid = Energy produced from ketolysis: 1 NADHH =2.5 ATP 2 ACETYL CoA = 20 ATP 1 ATP Loss 22.5-1=21.5 ATP  Ketosis Definition: When the rate of ketogenesis by the liver exceed the oxidative mechanism by which the extra- hepatic tissues oxidize the ketone bodies , their level will increased in the blood above the normal "ketonaemia" & this lead to increased their excretion in urine above the normal "ketonuria". Ketosis = ketonaemia + ketonuria.  Causes: I- Pathological causes: 1 Phlorhizin poisoning (inhibits glucose absorption). 2 D.M. 3 Renal glucosuria: due to excessive loss of carbohydrate in urine. II. Non-pathological causes: a) Starvation. b) Carbohydrate poor diet. c) High fat diet. d) Excessive exercise in post-absorptive phase. Mechanism: – Excessive lipolysis →↑ plasma free fatty acids →↑hepatic uptake of free fatty acids & ↑ β-oxidation & acetyl CoA production →↑ketogenesis.  Ketoacidosis Definition: – It is the type of metabolic acidosis that occurs due to ketosis. Mechanism: Ketone bodies are moderately strong acids. Increased ketone bodies in blood are neutralized by blood buffers mainly (HCO3-). This depletes bicarbonate and as a result blood PH isdecreased (acidosis). Effects: 1. Acidosis may cause transfer of k+ ions from intracellular fluid to blood causing hyperkalemia. 2. Dizziness & loss of concentration. 3. In severe cases of ketosis, coma may be developed.