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Lecture 11
Lipogenesis
Overview
glucose
Fat
ESTERIFICATION
GLUT-4
No GS
glucose
X
fatty acids
G6P
PPP
Consumes
reductant
and ATP
GLYCOLYSIS
Produces
reductant
LIPOGENESIS
pyruvate
acetyl-CoA
pyruvate
acetyl-CoA
PDH
Key steps (eg, GLUT-4, PDH,
lipogenesis) are stimulated when
insulin binds to its receptor on
the cell surface
KREBS
CYCLE
CO2
NADH release
ultimately
produces ATP
Pyruvate Dehydrogenase
• Oxidative decarboxylation of pyruvate
Pyruvate + CoA + NAD  acetyl-CoA + NADH + CO2
• Loss of carbon dioxide renders the reaction totally irreversible in vivo
– No pathways in humans to make acetate into ‘gluconeogenic’ precursors
• Can’t make glucose from acetyl-CoA
• No way of going back once the PDH reaction has happened
• Key watershed between carbohydrate and fat metabolism
• Regulated by reversible phosphorylation
– Active when dephosphorylated
• Inactivated by PDH kinase
• Activated by PDH phosphatase
– Insulin stimulates PDH phosphatase
• Insulin thus stimulates dephosphorylation and activation of PDH
• Note about Coenzyme A
– Often written as CoA-SH to emphasise that the functional part of the
molecule is the sulphydryl group
– Forms thioesters which are, themselves, quite ‘high energy’ bonds
– Most common carrier of fatty acids and acetates
Fate of Acetyl-CoA
• Burnt in the Krebs Cycle
– Stays in the mitochondria
– Carbon atoms fully oxidised to CO2
– Lots of NADH produced to generate ATP
• Lipogenesis
– Moved out into the cytoplasm
– Activated for fat synthesis
• In both cases the first step is citrate formation
– Condensation of acetyl-CoA with oxaloacetate
• Catalysed by citrate synthase
• Relies on fact that methyl hydrogens in acetyl-CoA come off, leaving –ve
charged carbon that attacks the carbonyl-carbon in oxaloacetate
– Regenerates Coenzyme A
– Citrate is a tricarboxylic acid
• It can be transported out of the mitochondria via carriers in the inner
mitochondrial membrane or can be sent into the next reaction of the Krebs
Cycle
• The ‘fate’ will depend on the need for energy (ATP/energy charge) and the
stimulus driving lipogenesis
ATP-Citrate Lyase
• Once in the cytoplasm, the citrate is cleaved
– By ATP-Citrate Lyase (ACL)
– Using CoA to generate acetyl-CoA and oxaloacetate
• Reaction requires ATP  ADP + phosphate
• ACL is inhibited by hydroxy-citrate (OHCit)
– OHCit is found in the Brindleberry
– Sold as a fat synthesis inhibitor
– Would we expect it to prevent the formation of fatty acids
• And, if so, would that actually help us lose weight?
• Oxaloacetate produced by ACL needs to return ot the matrix
– Otherwise the mitochondrial oxaloacetate pool becomes depleted
– Remember, oxaloacetate is really just a ‘carrier’ of acetates
• Both in the Krebs's cycle and in the transport of acetyl-CoAs into the
cytoplasm
– Oxaloacetate cannot cross the inner mitochondrial membrane
• Some interesting interconversions occur to get it back in!
Acetyl-CoA Carboxylase
• Activates acetyl-CoA and ‘primes’ it for lipogenesis
• Unusual in that it ‘fixes’ carbon dioxide
– In the form of bicarbonate
– A carboxylation reaction
Acetyl-CoA + CO2  malonyl-CoA
– Reaction requires ATP  ADP + phosphate
– Participation of the cofactor, biotin
• Biotin is involved in other carboxylation reactions
• ACC is stimulated by insulin
– Malonyl-CoA is committed to lipogenesis
• Pattern of phosphorylation is important in ACC
stimulation
– Also stimulated allosterically by citrate and inhibited allosterically
by long-chain fatty acyl-CoAs