AMP-activated protein kinase – Sterol regulatory element-binding protein 1c – Fatty acid synthase metabolic axis (AMPK-SREBP-1c-FASN axis)

The AMP-activated protein kinase (AMPK) – Sterol regulatory element-binding protein 1c (SREBP-1c) – Fatty acid synthase (FASN) metabolic axis is a central signaling pathway that regulates lipid metabolism and energy balance in response to cellular energy status (Hardie, J Intern Med, 2014). AMPK serves as the primary energy sensor, which, upon activation by a high AMP/ATP ratio or pharmacological agents, inhibits the master lipogenic transcription factor SREBP-1c to prevent the synthesis of fatty acids (Li et al., J Clin Invest, 2011). SREBP-1c is responsible for the transcriptional activation of Fatty acid synthase (FASN), the multi-enzyme protein that catalyzes the final steps of de novo lipogenesis (Horton et al., J Clin Invest, 2002). When AMPK is inactive, SREBP-1c is processed and moves to the nucleus to drive FASN expression, leading to increased lipid accumulation and potential lipotoxicity. This axis is frequently dysregulated in metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes, where excessive lipogenesis contributes to hepatic steatosis and insulin resistance (Postic & Girard, J Clin Invest, 2008). Furthermore, many cancers upregulate this axis to meet the high demand for membrane synthesis and signaling lipids required for rapid proliferation (Menendez & Lupu, Nat Rev Cancer, 2007). Therapeutic targeting of this axis involves AMPK activators like metformin, which indirectly suppress FASN, or direct inhibitors of FASN such as denifanstat, which are currently in clinical trials for NASH (Loomba et al., Lancet Gastroenterol Hepatol, 2021). Modulating this pathway offers a multi-pronged approach to treating metabolic syndrome by improving insulin sensitivity and reducing hepatic fat content.

Other names

AMPK/SREBP-1c/FASN pathwayAMPK-SREBP1c-FASN signaling axisAMPK-mediated lipogenic pathway

AMPK activation inhibits SREBP-1c processing and nuclear translocation, which reduces the transcriptional expression of FASN, thereby decreasing de novo lipogenesis; direct FASN inhibition blocks the enzymatic conversion of acetyl-CoA and malonyl-CoA into long-chain fatty acids (Li et al., J Clin Invest, 2011; Loomba et al., Lancet Gastroenterol Hepatol, 2021).