De novo fatty acid synthesis / lipogenesis (ACLY -> ACACA/ACACB -> FASN -> OLAH)

De novo lipogenesis builds long-chain saturated fatty acids (chiefly palmitate, C16:0) from carbohydrate- derived carbon in the cytosol, supplying membrane lipids, storage triacylglycerol and signalling precursors. Citrate exported from mitochondria is cleaved by ATP-citrate lyase (ACLY) to regenerate cytosolic acetyl-CoA (plus oxaloacetate); this acetyl-CoA also feeds cholesterol synthesis and protein acetylation. Acetyl-CoA carboxylase then carboxylates acetyl-CoA to malonyl-CoA in the committed, rate- limiting step - a biotin-dependent reaction carried out by two isozymes with distinct roles: the cytosolic ACACA (ACC1) supplies malonyl-CoA for fatty acid synthesis, whereas ACACB (ACC2), anchored at the mitochondrial outer membrane, makes a malonyl-CoA pool that inhibits carnitine palmitoyltransferase 1 and thereby restrains fatty acid beta-oxidation. Fatty acid synthase (FASN), a homodimeric multifunctional megaenzyme, then condenses one acetyl-CoA primer with seven malonyl-CoA units in iterative NADPH-dependent cycles - using its ketoacyl-synthase, malonyl/acetyl-transacylase, ketoacyl-reductase, dehydratase, enoyl- reductase, acyl-carrier and thioesterase activities - to produce palmitate. The auxiliary thioesterase OLAH (thioesterase II) can release medium-chain fatty acids early from the FASN acyl-carrier, shifting the product spectrum (e.g. in lactating mammary gland). ACLY, ACACA and FASN are central to lipogenic tissues and are cancer and metabolic-disease drug targets.