De Novo Fatty Acid Synthesis
Cytoplasmic synthesis of palmitate from acetyl-CoA and malonyl-CoA.
Overview
Fatty acid synthesis occurs in the cytoplasm using acetyl-CoA (exported from mitochondria as citrate). ACC (acetyl-CoA carboxylase) catalyzes the committed step, forming malonyl-CoA. Fatty acid synthase (FAS), a large multifunctional enzyme, performs seven cycles of condensation, reduction, dehydration, and reduction to build the 16-carbon palmitate. NADPH from the pentose phosphate pathway and malic enzyme provides reducing equivalents. SREBP-1c transcriptionally activates lipogenic genes in response to insulin.
Cellular Location
Cytoplasm (liver, adipose tissue, lactating mammary gland)
Clinical Significance
FASN overexpression in many cancers (lipogenic phenotype); ACC inhibitors in clinical trials for NASH and cancer; de novo lipogenesis contributes to fatty liver disease; malonyl-CoA inhibits CPT-I, coordinating synthesis with oxidation.