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Transcript
NME2.29: FAT AND CARBOHYDRATE METABOLISM IN THE FASTED STATE 06/03/08 LIPOLYSIS Triglycerides stored in adipose tissue can be degraded to form fatty acids and glycerol o Hormone-sensitive lipase catalyses this process o Insulin inhibits the enzyme inhibiting lipolysis o Adrenaline, glucagon and cortisol stimulate the enzyme promoting lipolysis Insulin deficiency results in uncontrolled lipolysis and hence weight loss FATTY ACID METABOLISM Fatty acids mobilised by lipolysis are exported from adipocytes to liver and muscle o In the cytosol fatty acids are combined with coenzyme A to form acyl-CoA o This conversion is coupled to transport into the mitochondria by acyl-CoA synthase Carnitine is used to transport acyl-CoA into mitochondrial matrix (from the inter-membrane space) o This transport process is inhibited by malonyl-CoA from fatty acid synthesis o Malonyl-CoA is present in high concentrations in the fed state Acyl-CoA is gradually degraded in the mitochondria through β-oxidation o Sequence of enzymatic reactions resulting in production of FADH2, NADH and acetyl-CoA o Each cycle removes two carbon atoms from the fatty acyl chain Most of the acetyl-CoA produced enters the TCA cycle o Some is used in the liver for ketogenesis – see below LEARNING OUTCOMES Describe the roles of glycogenolysis and gluconeogenesis in maintaining blood glucose homeostasis Blood glucose homeostasis is maintained principally by the liver through: o Glycogenolysis – breakdown of glycogen to form glucose o Gluconeogenesis – biosynthesis of glucose from substrates when glycogen stores are low Gluconeogenesis requires ATP and is conducted in the liver from a number of substrates: o Lactate – Cori cycle o Amino acids – all except leucine and lysine o Glycerol – e.g. from lipolysis Substrates are initially converted to pyruvate which is taken into the mitochondria o Pyruvate carboxylase (PC) converts pyruvate to oxaloacetate o Acetyl-CoA from fatty acid oxidation acts as an allosteric activator of PC o Oxaloacetate is then converted to malate o Malate is exported from the mitochondria and re-converted into oxaloacetate PEPCK converts oxaloacetate into phosphoenolpyruvate Phosphoenolpyruvate then undergoes ‘reverse glycolysis’ eventually to form glucose Describe specific examples of substrates for the gluconeogenesis pathway During fasting there are low insulin and high glucagon and cortisol levels o Glycerol is released by adipose tissue o Amino acids are released by muscle o Gluconeogenic enzymes are synthesised in the liver Explain why defects in mitochondrial fatty acid oxidation sometimes manifest as hypoglycaemia Fatty acid oxidation produces acetyl-CoA that allosterically activates pyruvate carboxylase Pyruvate carboxylase is a crucial enzymes in gluconeogenesis Defects in fatty acid oxidation may reduce production of acetyl-CoA and hence inhibit gluconeogenesis If the body cannot synthesise glucose ‘on demand’ during fasting then hypoglycaemia ensues Explain the function of ketone bodies Acetyl-CoA from fatty acid metabolism is used in ketogenesis which only occurs in the liver o Sequence of enzymatic reactions resulting in production of acetoacetate / 3-hydroxybutyrate o HMG-CoA lyase, the enzyme that produces acetoacetate, is only found in the liver Ketone bodies are synthesised in starvation and diabetes in response to: o High levels of circulating free fatty acids (e.g. from lipolysis) o Low insulin concentration The function of ketone bodies is to provide energy to muscle and more importantly to the brain o Succinyl-CoA transferase converts them back to acetyl-CoA which enters the TCA cycle o Unlike fatty acids, ketone bodies can cross the blood-brain barrier o Since they are only produced in the liver, the liver cannot metabolise ketone bodies Excessive ketogenesis causes a metabolic acidosis