ketosis- causes and consequences

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Ketosis- causes and consequences

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  • 1.KETOSIS- CAUSESAND10/21/2012CONSEQUENCESBiochemistry For MedicsBiochemistry for Medicswww.namrata.co1

2. Ketone Bodies Ketone bodies can be regarded as water-soluble,transportable form of acetyl units. Fatty acids are released by10/21/2012adipose tissue and converted into acetyl units by the liver,which then exports them as ketone bodies. Acetoacetate, D(-3) hydroxy butyrate (Beta hydroxyBiochemistry For Medicsbutyrate), and acetone are often referred to as ketone bodies2 3. KetogenesisKetogenesis takes place in liver using Acetyl co A as asubstrate or a precursor molecule. 10/21/2012 Enzymes responsible for ketone body formation areassociated mainly with the mitochondria Biochemistry For MedicsStepsTwo molecules of acetyl CoA condense to form acetoacetylCoA. This reaction, which is catalyzed by thiolase, is thereverse of the thiolysis step in the oxidation of fatty acids. 3 4. Ketogenesis Acetoacetyl CoA then reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and 10/21/2012 CoASH. The reaction is catalyzed by HMG co A synthase. Biochemistry For Medics This enzyme is exclusively present in liver mitochondria. There are two isoforms of this enzyme-cytosolic and mitochondrial. The mitochondrial enzyme is needed for ketogenesis while the cytosolic form is associated with cholesterol biosynthesis. 4 5. KetogenesisThis condensation resembles the one catalyzed by citrate synthase. 10/21/2012 This reaction, which has a favorable equilibrium owing to the hydrolysis of a thioester linkage, Biochemistry For Medics compensates for the unfavorable equilibrium in the formation of acetoacetyl CoA. 3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate in the presence of HMG Co A lyase .The carbon atoms split off in the acetyl-CoA molecule are derived from the original Acetoacetyl- 5 CoA molecule. 6. Biochemistry For Medics 10/21/20126 7. Ketogenesis Both enzymes(HMG CoA Synthase and HMG Co A Lyase) must be present in mitochondria for ketogenesis to take 10/21/2012 place.This occurs solely in liver and rumen epithelium, Biochemistry For Medics The sum of these reactions is-The other two ketone bodies-Acetone and D(-)- 3-Hydroxybutyrate are formed from Acetoacetate, theprimary ketone body. 7 8. Formation of Acetone Acetone is formed by decarboxylation in the presence ofdecarboxylase enzyme and, because it is a beta-keto10/21/2012acid, acetoacetate also undergoes a slow, spontaneousdecarboxylation to acetone.Biochemistry For Medics The odor of acetone may be detected in the breath of aperson who has a high level of acetoacetate in theblood. Acetone-breath has been used as a crude methodof diagnosing individuals with untreated Type Idiabetes mellitus.8 9. Formation of -Hydroxy Butyrate D (-)-3-Hydroxybutyrate (-Hydroxy Butyrate) is formed bythe reduction of acetoacetate in the mitochondrial matrix by10/21/2012D(-)3-hydroxybutyrate dehydrogenase. D(-)-3-Hydroxybutyrate is quantitatively the predominantketone body present in the blood and urine in ketosis.Biochemistry For MedicsThe -hydroxybutyrate dehydrogenase reaction has twofunctions: 1) it stores energy equivalent to an NADH in theketone body for export to the tissues, and2) it produces a more stable molecule.The ratio of hydroxybutyrate to acetoacetate depends onthe NADH/NAD+ ratio inside mitochondria. If NADHconcentration is high, the liver releases a higher proportion 9of -hydroxybutyrate. 10. Why are three enzymes requiredto synthesize acetoacetate? An enzyme that cleaves the thioester bond of the thiolase product acetoacetyl-CoA would also produce 10/21/2012 acetoacetate, but such a thioesterase does not seem to exist. Biochemistry For Medics However, the pathway that does exist is not especially wasteful; the third acetyl-CoA used merely acts catalytically Because the cell needs to have HMG-CoA synthase for other purposes, the choice is in having HMG-CoA lyase It is possible that having two mitochondrial enzymes (HMG-CoA synthase and HMG-CoA lyase) required for 10 ketone body synthesis assists in controlling the pathway. 11. Utilization of ketone bodies Ketone bodies serve as a fuel for extra hepatic tissuesThe ketone bodies are water soluble and are transported 10/21/2012 across the inner mitochondrial membrane as well as across the blood-brain barrier and cell membranes. Biochemistry For MedicsThey can be used as a fuel source by a variety of tissues including the CNS. They are preferred substrates for aerobic muscle and heart, thus sparing glucose when they are available.Tissues that can use fatty acids can generally use ketone bodies in addition to other energy sources. The exceptions are the liver and the brain.11 12. Utilization of ketone bodiesKetone bodies are utilized by extrahepatic tissues via a series ofcytosolic reactions that are essentially a reversal of ketone body 10/21/2012synthesis, the ketones must be reconverted to acetyl CoA in themitochondria:Utilization of Beta-hydroxybutyrate Biochemistry For Medics1) Beta-hydroxybutyrate, is first oxidized to acetoacetate with the production of one NADH (1).2) Under conditions where tissues are utilizing ketones for energy production their NAD+/NADH ratios are going to be relatively high, thus driving the -hydroxybutyrate dehydrogenase catalyzed reaction in the direction of acetoacetate synthesis. 12 13. Utilization of ketone bodies2) Coenzyme A must be added to the acetoacetate. The thioester bond is a high energy bond, so ATP equivalents10/21/2012must be used.In this case the energy comes from a trans esterification ofBiochemistry For Medicsthe CoAS from Succinyl CoA to acetoacetate by Coenzyme Atransferase, also called Succinyl co A : Acetoacetate co Atransferase, also known as Thiophorase.The Succinyl CoA comes from the TCA cycle.This reaction bypasses the Succinyl CoA synthetase step of theTCA cycle, hence there is no GTP formation at this stepsalthough it does not alter the amount of carbon in the cycle.13 14. Utilization of ketone bodies 10/21/2012 Biochemistry For MedicsThe liver has acetoacetate available to supply to other organs because it14lacks the particular CoA transferase and that is the reason that Ketonebodies are synthesized in the liver but utilized in the peripheral tissues. 15. Liver v/s Peripheral tissuesfor ketones as fuel molecules The enzyme, Succniyl co A Acetoacetate co A transferase, 10/21/2012also known as Thiophorase, is present at high levels in mosttissues except the liver. Importantly, very low level of enzyme expression in the liver Biochemistry For Medicsallows the liver to produce ketone bodies but not to utilizethem. This ensures that extra hepatic tissues have access to ketonebodies as a fuel source during prolonged fasting andstarvation, and Also, lack of this enzyme in the liver prevents the futile cycleof synthesis and breakdown of acetoacetate. 15 16. Regulation of KetosisKetogenesis is regulated at three steps-1) Lipolysis in Adipose tissue10/21/2012 Ketosis does not occur unless there is an increase in the level of circulating free fatty acids that arise from lipolysis ofBiochemistry For Medics triacylglycerol in adipose tissue. When glucose levels fall, lipolysis induced by glucagon secretion causes increased hepatic ketogenesis due to increased substrate (free fatty acids) delivery from adipose tissue. Conversely, insulin, released in the well-fed state, inhibits ketogenesis via the triggering dephosphorylation and inactivation of adipose tissue hormone sensitive lipase16 (HSL). 17. Lipolysis in Adipose tissue10/21/2012Biochemistry For Medics Hormone sensitive lipase exists in two forms inactive dephosphorylated (brought by Insulin) and active phosphorylated17 form (brought by glucagon, ACTH and catecholamines). Insulin promotes lipogenesis while the other hormones promote lipolysis. 18. Regulation of Ketosis2) Fate of fatty acid-free fatty acids are either oxidized to CO2 orketone bodies or esterified to triacylglycerol and 10/21/2012phospholipids. There is regulation of entry of fatty acids into the oxidativepathway by carnitine Acyl transferase-I (CAT-I) Biochemistry For Medics Malonyl-CoA, the initial intermediate in fatty acidbiosynthesis formed by acetyl-CoA carboxylase in the fedstate, is a potent inhibitor of CAT-I . Under these conditions, free fatty acids enter the liver cell inlow concentrations and are nearly all esterified toacylglycerols and transported out of the liver in very lowdensity lipoproteins (VLDL). 18 19. Regulation of CAT-1 activity 10/21/2012 Biochemistry For Medics CAT-I activity is low in the fed state, leading to depression 19 of fatty acid oxidation. However, CAT-1 activity is higher in starvation, allowing fatty acid oxidation to increase. 20. Regulation of Ketosis3) Fate of Acetyl co A The acetyl-CoA formed in beta-oxidation is oxidized in the 10/21/2012citric acid cycle, or it enters the pathway of ketogenesis toform ketone bodies. As the level of serum free fatty acids is raised, Biochemistry For Medicsproportionately more free fatty acids are converted to ketonebodies and less are oxidized via the citric acid cycle to CO2. Entry of acetyl CoA into the citric acid cycle depends on theavailability of Oxaloacetate for the formation of citrate, butthe concentration of Oxaloacetate is lowered if carbohydrateis unavailable or improperly utilized. 20 21. Regulation of Ketosis- Overview10/21/2012Biochemistry For Medics21 During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-Co A are generated. These exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies. 22. Biological significance of ketonebodiesKetone bodies serve as a fuel for extra hepatic tissuesBrain10/21/2012 It is metabolically active and metabolically privileged. The brain generally uses 60-70% of total body glucoseBiochemistry For Medicsrequirements, and always requires some glucosefor normal functioning. Under most conditions, gl

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