Lipogenesis

• In lipogenesis, FAs are synthesised from acetyl-CoA
• why is most of the acetyl-CoA used for lipogenesis derived from glucose?

  because insulin is the main stimulant
• lipogenesis requires NADPH for reducing power
• NADPH is produced from the pentose phosphate pathway
• Lipogenesis is a wholly cytosolic process
• Glycerol 3-phosphate is used for esterification
• Acetyl-CoA carboxylase carboxylates acetyl-CoA (from bicarbonate) to form malynol-CoA
• What is the only step in lipogenesis that requires ATP?

  Acetyl-CoA carboxylation by ACC
• ACC = acetyl-CoA carboxylase
• ACC is regulated by many factors:

  • Stimulated by insulin
  • Stimulated allosterically by citrate
  • Inhibited allosterically by fatty acyl-CoA
• Lipogenesis requires reduction, dehydration, reduction
• Fatty acid synthase

  1. Malonyl CoA and acetate bind to FAS covalently
  2. Malonyl CoA decarboxylates, leaving it with a negative charge
  3. The charge on malonyl CoA attracts the slight positive charge on acetate, bringing them together to add acetate to the chain
  4. NADPH reduces two carbon double bonds
• Each round of adding two carbons requires:

  • 2 molecules of NADPH, but no ATP
  • The release of the carbon dioxide used to produce malonyl-CoA
• FAs are released from FAS when the chain is about 14-18 carbons long
• FAS = fatty acid synthase
• Desaturation of double bonds is done after release from FAS
• in the body, double bonds cannot be added after C9
• Only the liver has glycerol kinase, so G6P must be stolen from glycolysis in the liver for fatty acid esterification
• FAS expression is downregulated when there is a lot of fat around
• We need PDH to be activated to produce acetyl-CoA
• why is acetyl-CoA required for lipogenesis?

  1. conversion to malynol-CoA
  2. continue in Kreb's cycle to produce ATP required
• Citrate can easily move from the mitochondria to the cytoplasm
• Once in the cytoplasm, ATP-citrate lyase uses CoA to cleave citrate into oxaloacetate and acetyl-CoA, using an ATP in the process
• after citrate transport oxaloacetate needs to return to the matrix, but cannot cross the inner mitochondrial membrane
• How does oxaloacetate re-enter the matrix after transport?

  1. Oxidised by NADH to produce malate
  2. Oxidised (reducing NADPH) to become pyruavate
  3. Pyruvate re-enters the matrix
• Citrate transport to the cytoplasm activates ACC
• Malonyl-CoA inhibits CAT-1, which is the enzyme that swaps CoA for carnitine on FAs

  • Therefore prevents FA transport into mitochondria
• How does insulin inhibit FA oxidation?

  Insulin stimulates ACC to increase malonyl production, which inhibits CAT-1 which transports FAs into the mitochondria for oxidation
• NADPH is a form of NADH involved in anabolic reactions
• NADPH has the same chemical properties of NADH, but is bound by different enzymes
• The Pentose Phosphate Pathway produces NADPH in direct proportion for its demand in lipogenesis
• the key regulatory enzyme of the pentose phosphate pathway is G6PDH
•  G6PDH

  • Takes G6P out of glycolysis to make two NADPH
  • This produces a five carbon sugar
• How is the 5C sugar from the pentose phosphate pathway returned to glycolysis?

  rearranging and exchanging carbon atoms between several 5C molecules to make C6 and C3 molecules
• G6PDH is stimulated by the demand for NADP
• Insulin stimulates GLUT-4, PDH, and ACC

  • Also switches on enzymes for FAS and esterification enzyme
• The Kreb's Cycle responds to increased ATP demand (used during activation and transport)
• Glycerol 3-P is provided from glycolysis

  • But can also come from pyruvate by gluconeogenesis (glycerolneogenesis)