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Transcript
Utilization of ketone bodies by peripheral tissues Lec. 4 - Ketogenesis (Biosynthesis of ketone bodies) • In humans, liver mitochondria has capacity to divert any excess acetyl-CoA formed in the liver during oxidation of fatty acids or oxidation of pyruvate that exceed capacity of citric acid cycle to the ketone bodies , where they can reconvert to acetyl CoA & oxidized by citric acid cycle. Why ketone bodies synthesized by the liver: The production and export of ketone bodies from the liver to extrahepatic tissues allow continued oxidation of fatty acids in the liver when acetyl-CoA is not being oxidized in the citric acid cycle. • Liver constantly produces low levels of ketone bodies, but their production becomes significant during starvation, when ketone bodies are needed to provide energy to the peripheral tissues. Liver actively produces ketone bodies, but it can't utilize it as a fuel because [can not reconvert acetoacetate to acetyl CoA] ,while in extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl CoA - acetoacetate CoA transferase which transfer CoA portion from succinyl-CoA to acetoacetate to form acetoacetyl-CoA . Ketone bodies are important sources of energy for the peripheral tissues because: 1) They are soluble in aqueous solution (don't need to be incorporated into lipoproteins or carried by albumin like lipid). 2) Produced in liver when acetyl-CoA present exceed the oxidative capacity of the liver. 3) They are used in proportion to their concentration in the blood by extrahepatic tissues (skeletal & cardiac muscle & renal cortex). 4) Brain, heart & muscle can use ketone bodies to meet their energy needs if the blood levels rise sufficiently (during prolonged periods of fasting). Utilization of ketone bodies including the following steps: 1) 3-hydroxy butyrate is oxidized to acetoacetate by 3-hydroxy butyrate dehydrogenase, producing NADH. 2) Acetoacetate receives a coenzyme A from succinyl CoA by the action of succinyl CoA - acetoacetate CoA transferase [succinyl CoA transferase] present in all tissues except the liver? Its absence allows the liver to produce ketone bodies but not utilize them; this ensures that extrahepatic tissues have access to ketone bodies as a fuel source during prolonged fasting & starvation. 3) Acetoacetyl CoA is actively removed by its conversion to two molecules of acetyl CoA by the action of thiolase. Synthesis of ketone bodies 1) Formation of acetoacetyl CoA can occur by one of 2 processes: a. Incomplete breakdown of fatty acid. b. Enzymatic condensation of two molecules of acetyl-CoA, which catalyzed by thiolase (the reversal of thiolase reaction of fatty acid oxidation). 2) The acetoacetyl-CoA, condenses with 3rd molecule of acetylCoA to form β -hydroxy- β -methylglutaryl-CoA (HMG-CoA) catalyzed by HMG-CoA synthase (the rate limiting step in the synthesis of ketone bodies & present in significant quantities only in the liver). 3) HMG-CoA is cleaved to free acetoacetate and acetyl-CoA catalyzed by HMG-CoA lyase. 4) The acetoacetate is reversibly reduced by D-β-hydroxybutyrate dehydrogenase with NADH as hydrogen donor to β–hydroxybutyrate or it can be spontaneously decarboxylated to form acetone. Note: D-β-hydroxy-butyrate dehydrogenase [mitochondrial enzyme, specific for the D stereoisomer; it does not act on L- β -hydroxyacyl-CoA and is not to be confused with L- β -hydroxyacyl-CoA dehydrogenase of the β-oxidation pathway. Ketogenesis is regulated at three crucial steps: 1) Partition of acetyl-CoA between the pathway of ketogenesis and the citric acid cycle. • Fall in concentration of oxaloacetate, within the mitochondria, impair the ability of the citric acid cycle to metabolize acetylCoA and divert fatty acid oxidation toward ketogenesis. Because increase in the [NADH]/[NAD+] ratio caused by increased β-oxidation affecting the equilibrium between oxaloacetate and malate and decreasing the concentration of oxaloacetate. 8 2) Free fatty acid mobilization from adipose tissue; directly affects the level of ketogenesis the factors regulating mobilization of free fatty acids from adipose tissue are important in controlling ketogenesis. 3) The activity of carnitine palmitoyl transferase- I in liver, which determines the proportion of the fatty acid flux that is oxidized rather than esterified; HOW • CPT-I activity is low in the fed state, leading to decrease fatty acid oxidation, and , high in starvation, allowing fatty acid oxidation to increase • Malonyl-CoA, formed by acetyl-CoA carboxylase in the fed state, is a potent inhibitor of CPT-I. • Concentration of free fatty acids increases with the onset of starvation, acetyl- CoA carboxylase is inhibited and malonylCoA decreases, CPT-I transport more of acyl-CoA to mitochondria to be oxidized (increase production of AcetylCoA). • These events are reinforced in starvation by decrease in the [insulin]/[glucagon] ratio. Lec. 5 - Ketosis Higher level of ketone bodies than normal present in the blood (ketonemia) or urine (ketonuria). Ketoacidosis: increase acidity of the blood due to presence of high concentration of ketone bodies. ketone bodies are moderately strong acids and buffered with alkali reserve (plasma bicarbonate) when present in blood but their continuous production in large quantity progressively depletes this reserve, causing ketoacidosis . The higher ketone bodies conc. in the blood or urine due to increased production by liver rather than decrease in their utilization by extrahepatic tissues. Ketoacidosis develops from excessive production of acetyl – CoA due to body attempts to obtain energy from stored fat in the absence of adequate carbohydrate metabolites. This condition reinforced by : Inadequate incorporation of acetylCoA into TCA due to decrease of the oxaloacetate concentration Ketosis reflects excessive use of fat due to: 1- Intracellular glucose deficiency 2- Low insulin level & activity: How This will increase rate of production of gluconeogenic substrate by glycolysis & proteolysis & rate of hepatic gluconeogenesis. Lead to increase rate of glucose released into the extracellular, this is appropriate in starvation, but aggravates the hyperglycemia in DM. ketosis can be reversed by restoring adequate of carbohydrate metabolism. 1) In starvation: Restorations consist of adequate carbohydrate ingestion. 2) In diabetic ketosis : can be reversed by insulin administration ,which permits circulating blood glucose to be taken up by the cells ,with production of oxaloacetate (the acceptor of acetyl –CoA ), normal metabolism is restored & decrease release of FA from adipose tissues . 9