Adenosine monophosphate-activated protein kinase–Acetyl-CoA carboxylase pathway (AMPK–ACC pathway)

The AMPK–ACC pathway is a fundamental metabolic signaling axis that serves as a master regulator of cellular energy balance [1, 5]. Adenosine monophosphate-activated protein kinase (AMPK) functions as an energy sensor that is activated under conditions of low cellular energy, such as fasting or exercise, characterized by an increased AMP/ATP ratio [2, 11]. Upon activation, AMPK phosphorylates and inhibits Acetyl-CoA carboxylase (ACC), which exists in two primary isoforms: ACC1, involved in de novo lipogenesis, and ACC2, which regulates fatty acid oxidation [3, 9]. The inhibition of ACC leads to a decrease in malonyl-CoA levels, which simultaneously suppresses fatty acid synthesis and relieves the inhibition of carnitine palmitoyltransferase 1 (CPT1), allowing for increased mitochondrial fatty acid oxidation [1, 15]. This pathway is a key therapeutic focus for treating metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis (NASH), by promoting a shift toward energy expenditure [5, 16]. Drugs targeting this axis include indirect AMPK activators like metformin, direct AMPK activators such as PXL770, and direct ACC inhibitors like firsocostat [4, 7, 14].

Other names

AMPK/ACC axisAMPK-mediated ACC inhibitionAMPK-ACC signalingAMPK-ACC metabolic axis

Activation of AMPK leads to the inhibitory phosphorylation of ACC1 and ACC2, which reduces malonyl-CoA levels, thereby decreasing fatty acid synthesis and increasing mitochondrial fatty acid oxidation [1, 2, 3].