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:
- Condensation: Acetyl-ACP + Malonyl-ACP → Acetoacetyl-ACP + CO₂
- Reduction: → β-Hydroxyacyl-ACP (uses NADPH)
- Dehydration: → Enoyl-ACP + H₂O
- 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.