Adenosine monophosphate-activated protein kinase–Sterol regulatory element-binding protein 1 signaling pathway (AMPK–SREBP-1 pathway)

The AMPK–SREBP-1 pathway is a central regulatory mechanism that couples cellular energy status to lipid biosynthesis. Adenosine monophosphate-activated protein kinase (AMPK) serves as the primary energy sensor, becoming activated during states of energy depletion (Li et al., 2011, Nature Medicine). Once active, AMPK directly phosphorylates Sterol regulatory element-binding protein 1 (SREBP-1), specifically the SREBP-1c isoform, at the Ser372 residue. This phosphorylation event prevents the proteolytic cleavage of SREBP-1 in the Golgi apparatus, thereby blocking its translocation into the nucleus where it would otherwise act as a transcription factor for lipogenic genes (Eberle et al., 2004, Journal of Clinical Investigation). By inhibiting SREBP-1, AMPK effectively suppresses de novo lipogenesis and the expression of enzymes like Fatty Acid Synthase (FASN) and Acetyl-CoA Carboxylase (ACC). This pathway is frequently impaired in metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, leading to excessive fat accumulation in tissues (Zhou et al., 2001, Journal of Clinical Investigation). Therapeutic strategies often focus on AMPK activators, such as metformin or novel small molecules, to restore this inhibitory control over lipid synthesis. Furthermore, the pathway is a target of interest in cancer research, as many tumors upregulate SREBP-1 to meet the high demand for lipids required for rapid cell proliferation (Kamisuki et al., 2009, Chemistry & Biology).

Other names

AMPK/SREBP-1c axisAMPK-SREBP1 signalingAMPK-mediated SREBP-1 inhibition

Activation of AMPK leads to the inhibitory phosphorylation of SREBP-1 at Ser372, preventing its proteolytic maturation and nuclear translocation, which suppresses the transcription of lipogenic enzymes.