Metabolism of Ketone Bodies PDF

25 Metabolism of Ketone Bodies ILOs By the end of this lecture, students will be able to 1. 2. 3. 4. - Describe the process of ketone body synthesis Outline the ketolysis pathway Correlate the regulation of KB synthesis and breakdown to different clinical conditions Deduce the metabolic alterations...

25 Metabolism of Ketone Bodies ILOs By the end of this lecture, students will be able to 1. 2. 3. 4. - Describe the process of ketone body synthesis Outline the ketolysis pathway Correlate the regulation of KB synthesis and breakdown to different clinical conditions Deduce the metabolic alterations in ketotic state ❖ Ketone body synthesis (Ketogenesis): (Figure 1) Ketone bodies are considered the alternative fuel for the body. When the level of acetyl CoA from β-oxidation increases in excess of that required for entry into the citric acid cycle, it undergoes ketogenesis in the mitochondria of liver (ketone body synthesis). - The three compounds: acetoacetate, β-hydroxybutyrate, and acetone are collectively known as ketone bodies. - Under normal fed state, the hepatic production of acetoacetate and β-hydroxybutyrate is minimal and the concentration of these compounds in the blood is very low (does not exceed 3 mg/dl). - Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies. This increases dramatically in cases of starvation - Ketone bodies are important sources of energy for the peripheral tissues. Why? 1) They are soluble in aqueous solution and, therefore, do not need to be incorporated into lipoproteins or carried by albumin as do the other lipids 2) They are produced in the liver during periods when the amount of acetyl CoA present exceeds that required by CAC 3) Are used in proportion to their concentration in the blood by extrahepatic tissues, such as skeletal and cardiac muscle, the intestinal mucosa, and the renal cortex. Even the brain can use ketone bodies to help meet its energy needs if the blood levels rise sufficiently. Thus, ketone bodies spare glucose, which is particularly important during prolonged periods of fasting - 1 1- 3-hydroxy-3-methylglutaryl (HMG) CoA synthase combines a third molecule of acetyl CoA with acetoacetyl CoA to produce HMG CoA. 2- HMG CoA synthase is the rate-limiting step in the synthesis of ketone bodies and is present in significant quantities only in the liver. Regulation of ketone bodies synthesis: HMG COA synthase is the regulatory enzyme 1234- Activity increased fatty acids in the blood. Glucagon hormone activates HMG-CoA Insulin inhibits HMG-CoA Also inhibited by high level of CoASH. When fatty acids flow to the liver, CoASH is used for its activation. Thus, CoASH levels are reduced and HMG COA synthase is active. Figure1 : Ketogenesis process - ❖ Ketone body use by the peripheral tissues: Ketolysis (Figure 2) Although the liver constantly synthesizes low levels of ketone bodies, their production increases during fasting when ketone bodies are needed to provide energy to the peripheral tissues. - In the fasting state or in cases of uncontrolled diabetes mellitus (insulin deficiency). Ketone bodies are utilized as a fuel by muscles (cardiac and skeletal), brain and kidneys in prolonged starvation - Utilization of ketone bodies requires that acetoacetate is reactivated forming acetoacetyl CoA. This is done by a mitochondrial enzyme thiophorase presents in nonhepatic tissues (but absent from liver) that uses succinyl CoA as the source of the coenzyme A. 2 Figure 2: Ketolysis process - ❖ Ketosis and ketoacidosis Ketosis occurs when the rate of formation of ketone bodies is greater than the rate of their use, their levels begin to rise in the blood (ketonemia) and, eventually, in the urine (ketonuria) together with acetone odour in the breath. - Causes of Ketosis: 1. Starvation with depletion of carbohydrate stores results in increased fatty acid oxidation and ketosis. 2. Diabetic patients with uncontrolled blood glucose, invariably suffer from ketosis. In both cases there is lack of insulin, which brings about lipolysis and decreased utilization of glucose leading to increased KB synthesis. 3. Following strict ketogenic diet (very low carb diet with high fat and protein) This reduction in carbs increase lipolysis, using fat for energy. This huge amount of FFA dramatically increase kB synthesis and puts the body into a state of ketosis. Ketogenic diets can cause significant reductions in blood sugar and insulin levels. However, the high fat and protein intake has its health hazards. - The condition can get worse as Acetoacetic acid and β-hydroxybutyric acid are moderately strong acids. When these acids are present in the circulation, they must be buffered by the alkali reserve in the blood (HCO3). Their continual excretion in large quantities will lead to progressive depletion of the alkali reserve causing acidosis (ketoacidosis) (Figure 3) - The condition is common with uncontrolled diabetes leading to what is known as Diabetic ketoacidosis (DKA), which is a serious condition that can give rise to coma and death. 3 Figure 3: Ketoacidosis 4