Fatty Acid Synthesis

Fatty Acid Synthesis (Lipogenesis)

Fatty acid synthesis occurs in the cytosol of liver, adipose, lactating mammary gland, and adrenal cortex. It converts Acetyl-CoA (from glucose catabolism) into palmitate (C16:0) using NADPH as reductant.

Transfer of Acetyl-CoA from Mitochondria to Cytosol

Mitochondrial Acetyl-CoA cannot cross the inner membrane. It condenses with OAA → Citrate → exported to cytosol → cleaved by ATP-Citrate Lyase → Acetyl-CoA + OAA (OAA returns as malate or used for NADPH via malic enzyme).

Committed Step — ACC (Rate-Limiting)

Acetyl-CoA Carboxylase (ACC): Acetyl-CoA + CO₂ + ATP → Malonyl-CoA (requires Biotin).

  • This is the rate-limiting, committed step of FA synthesis
  • Activated by: Citrate (signals abundant Acetyl-CoA), Insulin (dephosphorylation)
  • Inhibited by: Palmitoyl-CoA (end-product feedback), Glucagon/Epinephrine (via phosphorylation by PKA), AMPK (low energy signal)
  • Malonyl-CoA also inhibits CPT-I → prevents FA oxidation simultaneously with synthesis

Fatty Acid Synthase (FAS) Complex

A large multifunctional enzyme in cytosol. Catalyzes 7 cycles of elongation to produce Palmitate (C16:0). Uses Acyl Carrier Protein (ACP) to hold intermediates. Each cycle adds 2 carbons from Malonyl-CoA and uses 2 NADPH:

  1. Condensation: Acetyl-ACP + Malonyl-ACP → Acetoacetyl-ACP + CO₂
  2. Reduction: → β-Hydroxyacyl-ACP (uses NADPH)
  3. Dehydration: → Enoyl-ACP + H₂O
  4. Reduction: → Saturated acyl-ACP (uses NADPH)

After 7 cycles: 1 Palmitate released by thioesterase.

To synthesize one Palmitate: 1 Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 7 ATP

Elongation and Desaturation

  • Elongation: In SER and mitochondria — extends palmitate to stearate (C18) and longer chains
  • Desaturation: In SER — Δ9 desaturase introduces double bonds; humans can only insert double bonds up to Δ9 → cannot synthesize ω-3 or ω-6 fatty acids (essential)

Comparison: Synthesis vs Oxidation

  • Location: Synthesis — Cytosol; Oxidation — Mitochondria
  • Carrier: Synthesis — ACP; Oxidation — CoA
  • Cofactors: Synthesis — NADPH; Oxidation — NAD+ and FAD
  • Transport: Synthesis — Citrate shuttle out; Oxidation — Carnitine shuttle in
  • Intermediates: Synthesis — D-isomers; Oxidation — L-isomers

Regulation by Insulin

Insulin: ↑Glucose uptake → ↑Acetyl-CoA → ↑Citrate → Activates ACC → FA synthesis ↑. Also activates ACC by dephosphorylation (inhibits AMPK). High-carbohydrate diet → de novo lipogenesis → hypertriglyceridemia.