Biochemistry · Metabolic pathway

Fatty acid synthesis (lipogenesis) !

With surplus sugar, the liver and fat tissue build fatty acids two carbons at a time, spending ATP and NADPH, up to palmitate.

Updated 2026-11-01

Interactive map

Balance: ATP -7nadph -14

Key facts

Takes place in the cytosol; the rate-limiting step is acetyl-CoA carboxylase (biotin), which forms malonyl-CoA.
Acetyl-CoA leaves the mitochondrion as citrate (citrate shuttle): ATP-citrate lyase splits it again in the cytosol.
Each fatty acid synthase turn: condensation → reduction → dehydration → reduction; adds 2 C.
Palmitate (16 C): 8 acetyl-CoA, 7 ATP and 14 NADPH.
Malonyl-CoA also blocks CPT-I: while fat is being made it is not burned.

In detail

Citrate shuttle: in the mitochondrion acetyl-CoA and oxaloacetate form citrate, which moves to the cytosol.
In the cytosol ATP-citrate lyase gives back acetyl-CoA and oxaloacetate (one ATP spent).
Oxaloacetate becomes malate and malic enzyme turns it into pyruvate, producing NADPH for synthesis.
ACC carboxylates acetyl-CoA to malonyl-CoA; malonyl/acetyl transacylase loads both onto the ACP of fatty acid synthase.
Seven turns of the cycle give palmitoyl-ACP and the thioesterase releases palmitate; elongation (ER) and desaturases do the rest.
Humans cannot place double bonds beyond carbon 9: linoleic (ω-6) and α-linolenic (ω-3) acids are essential.

Also called: De novo lipogenesis, Fatty acid synthase cycle

Regulation

Insulin activates ACC (dephosphorylation) and raises ACC and FAS amounts (via SREBP-1c).
Glucagon, adrenaline and AMPK phosphorylate and switch off ACC.
Citrate activates ACC; palmitoyl-CoA inhibits it.

The steps, one by one

Entry · Acetyl-CoA carboxylase (ACC) irreversible Acetyl-CoA + CO₂ + ATP → Malonyl-CoA + ADP + phosphate (Pi)Committed, rate-limiting step: carboxylates acetyl-CoA with bicarbonate to form malonyl-CoA, the two-carbon donor.If it fails: Biotin or biotinidase deficiency slows every carboxylase, ACC included.
Step 1 · Fatty acid synthase: β-ketoacyl synthase (KS) irreversible Acyl-ACP + Malonyl-ACP → β-Ketoacyl-ACP + CO₂Condensation: the growing acyl chain joins the malonyl loaded on the ACP and the CO₂ added by ACC leaves; the chain gains 2 C.If it fails: Losing CO₂ makes the condensation irreversible: that is why ATP is spent at ACC.
Step 2 · Fatty acid synthase: β-ketoacyl reductase (KR) β-Ketoacyl-ACP + NADPH ⇌ β-Hydroxyacyl-ACP + NADP⁺First reduction: NADPH turns the keto group into an alcohol (D-3-hydroxyacyl-ACP).If it fails: NADPH comes mainly from the pentose phosphate pathway and malic enzyme: without it synthesis stops.
Step 3 · Fatty acid synthase: dehydratase (DH) β-Hydroxyacyl-ACP ⇌ trans-Δ²-Enoyl-ACP + H₂ORemoves a water molecule and leaves a trans double bond between carbons 2 and 3 (enoyl-ACP).If it fails: It mirrors the β-oxidation hydratase, with the opposite isomer (D rather than L).
Step 4 · Fatty acid synthase: enoyl reductase (ER) irreversible trans-Δ²-Enoyl-ACP + NADPH → Acyl-ACP + NADP⁺Second reduction: another NADPH saturates the double bond; an acyl 2 C longer returns to condensation.If it fails: After seven turns the acyl has 16 C and moves to the thioesterase.
Exit · Fatty acid synthase: thioesterase (TE) irreversible Acyl-ACP + H₂O → PalmitateAt 16 carbons the thioesterase cuts the link to the ACP and releases palmitate.If it fails: FAS is overexpressed in many tumours, so thioesterase inhibitors are under study.

Clinical notes

A diet high in refined carbohydrate raises liver lipogenesis and contributes to fatty liver.
Fatty acid synthase is increased in several cancers and is a research target.
Biotin deficiency lowers the activity of ACC and the other carboxylases.

Pathways

Test yourself

Think of the answer, then tap the question to see it.

What is the rate-limiting step of fatty acid synthesis and which vitamin does it need?

Acetyl-CoA carboxylase, which forms malonyl-CoA; it uses biotin (B7).

How does acetyl-CoA leave the mitochondrion to make fat?

As citrate; in the cytosol ATP-citrate lyase splits it back into acetyl-CoA and oxaloacetate.

How much NADPH is spent to make one palmitate?

14 NADPH: two for each of the seven turns (one per reduction).

Why do synthesis and β-oxidation not run at the same time?

Malonyl-CoA from synthesis inhibits CPT-I, so acyl-CoA cannot enter the mitochondrion.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: Fatty acyl-CoA biosynthesis (Reactome, 2026); Fatty acid metabolism (Reactome, 2026); FASN: Fatty acid synthase (human) (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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