Fatty acid synthase and Acetyl-CoA carboxylase 1 (FASN and ACC1)

Fatty acid synthase (FASN) and Acetyl-CoA carboxylase 1 (ACC1) are the two primary enzymes responsible for de novo lipogenesis (DNL) in human cells [nih.gov, researchgate.net]. ACC1 catalyzes the rate-limiting step of converting acetyl-CoA into malonyl-CoA, which then serves as the primary substrate for FASN to synthesize long-chain saturated fatty acids, such as palmitate [nih.gov, microbiologyresearch.org]. While DNL is typically restricted to the liver and adipose tissue in healthy individuals, it is frequently upregulated in various cancers and metabolic disorders to support rapid cell proliferation and energy storage [nih.gov, biorxiv.org]. In oncology, these enzymes are considered metabolic oncogenes because they provide the lipids necessary for membrane synthesis and signaling in tumor cells [researchgate.net, nih.gov]. In metabolic diseases like metabolic dysfunction-associated steatohepatitis (MASH), inhibiting these enzymes reduces hepatic fat accumulation and inflammation [nih.gov]. Therapeutic strategies include selective inhibitors for each enzyme, such as denifanstat for FASN and firsocostat for ACC, which are being evaluated for their ability to disrupt lipid-dependent disease progression [biorxiv.org]. Notable safety concerns include skin and hair toxicity for FASN inhibitors and thrombocytopenia for ACC inhibitors [microbiologyresearch.org, biorxiv.org].

Other names

FASNACC1ACACAFASFatty acid synthaseAcetyl-CoA carboxylase 1

Inhibition of the de novo lipogenesis (DNL) pathway. ACC1 inhibitors block the conversion of acetyl-CoA to malonyl-CoA, while FASN inhibitors block the subsequent synthesis of long-chain fatty acids from malonyl-CoA and acetyl-CoA [nih.gov, biorxiv.org].