Lipogenesis

1
Lecture 11

• Lipogenesis

2
Overview
glucose
Fat
ESTERIFICATION
GLUT-4
No GS
X
fatty acids
glucose
G6P
Consumes reductant and ATP
GLYCOLYSIS
PPP
LIPOGENESIS
Produces reductant
pyruvate
acetyl-CoA
acetyl-CoA
pyruvate
PDH
Key steps (eg, GLUT-4, PDH, lipogenesis) are
stimulated when insulin binds to its receptor on
the cell surface
KREBS CYCLE
NADH release ultimately produces ATP
CO2
3
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
• Cant 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

4
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

5
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!

6
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