Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms Academic Article uri icon

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  • Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules1. LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation2-6. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1-containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. Thus, LCFA-CoA metabolites act as direct endogenous AMPK β1-selective activators and promote LCFA oxidation.


  • Pinkosky, Stephen L
  • Scott, John W
  • Desjardins, Eric M
  • Smith, Brennan K
  • Day, Emily A
  • Ford, Rebecca J
  • Langendorf, Christopher G
  • Ling, Naomi XY
  • Nero, Tracy L
  • Loh, Kim
  • Galic, Sandra
  • Hoque, Ashfaqul
  • Smiles, William J
  • Ngoei, Kevin RW
  • Parker, Michael W
  • Yan, Yan
  • Melcher, Karsten
  • Kemp, Bruce E
  • Oakhill, Jonathan S
  • Steinberg, Gregory

publication date

  • September 2020