Acetyl-CoA carboxylase (ACC) (ACC)

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA, the rate-limiting step in fatty acid biosynthesis (UniProt: Q13085). In humans, two isoforms exist: ACC1 (ACACA), which is cytosolic and drives de novo lipogenesis, and ACC2 (ACACB), which is localized to the mitochondrial membrane and regulates fatty acid oxidation by inhibiting carnitine palmitoyltransferase 1 (CPT1) (PubMed: 28803010). Malonyl-CoA serves as both a substrate for fatty acid synthase and a key metabolic signal that prevents the entry of fatty acids into the mitochondria for beta-oxidation. Pharmacological inhibition of ACC is a major therapeutic strategy for treating metabolic disorders, particularly metabolic dysfunction-associated steatohepatitis (MASH), by simultaneously reducing fat synthesis and promoting fat burning in the liver (PubMed: 32518015). By lowering malonyl-CoA levels, these inhibitors relieve the inhibition of CPT1, facilitating the transport of fatty acids into the mitochondria for energy production. Clinical trials of ACC inhibitors like firsocostat have demonstrated significant reductions in hepatic fat content. However, clinical development has faced challenges such as compensatory increases in serum triglycerides, likely mediated by the induction of sterol regulatory element-binding protein 1 (SREBP-1) (PubMed: 29203861). This target remains a high-interest area for metabolic and cardiovascular research due to its central role in lipid homeostasis.

Other names

ACACAACACBAcetyl-CoA carboxylase 1Acetyl-CoA carboxylase 2Biotin carboxylaseAcetyl-CoA carboxylase alphaAcetyl-CoA carboxylase beta

Inhibition of the conversion of acetyl-CoA to malonyl-CoA, thereby reducing de novo lipogenesis and increasing mitochondrial fatty acid oxidation.