Sterol regulatory element-binding protein 1 and Acetyl-CoA carboxylase (SREBP1/ACC)

The SREBP1/ACC designation refers to a critical regulatory axis in lipid metabolism consisting of the transcription factor Sterol Regulatory Element-Binding Protein 1 (SREBP1) and its downstream enzymatic target, Acetyl-CoA Carboxylase (ACC). SREBP1, specifically the SREBP-1c isoform, acts as a master regulator of de novo lipogenesis by inducing the expression of genes required for fatty acid synthesis, most notably ACC, which catalyzes the rate-limiting step of converting acetyl-CoA to malonyl-CoA (PubMed: 29211692). This pathway is frequently overactivated in metabolic disorders such as metabolic dysfunction-associated steatohepatitis (MASH) and certain cancers, where it drives the accumulation of toxic lipid species and provides building blocks for membrane synthesis (NIH: PMC6164305). Therapeutic strategies targeting this axis include direct small-molecule inhibitors of ACC (e.g., Firsocostat) to acutely block fatty acid production and SREBP activation inhibitors (e.g., Fatostatin) to suppress the entire lipogenic gene program (Nature Reviews Drug Discovery: 2021). While highly effective at reducing hepatic fat, pharmacological modulation of this axis requires careful monitoring of systemic lipid levels, as ACC inhibition can lead to paradoxical increases in serum triglycerides via SREBP-1c mediated feedback loops (PubMed: 29719235).

Other names

SREBP-1/ACC axisSREBF1/ACACA pathwaySterol regulatory element-binding transcription factor 1Acetyl-CoA carboxylase 1/2

Inhibition of ACC enzymatic activity to block the conversion of acetyl-CoA to malonyl-CoA, or inhibition of SREBP1 activation to downregulate the expression of lipogenic enzymes including ACC.