Download NME2.29 - Fat and Carbohydrate Metabolism 2

NME2.29: FAT AND CARBOHYDRATE METABOLISM IN THE FASTED STATE
06/03/08
LIPOLYSIS
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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
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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
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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
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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
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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
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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