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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.


    Stephen L Pinkosky, John W Scott, Eric M Desjardins, Brennan K Smith, Emily A Day, Rebecca J Ford, Christopher G Langendorf, Naomi X Y Ling, Tracy L Nero, Kim Loh, Sandra Galic, Ashfaqul Hoque, William J Smiles, Kevin R W Ngoei, Michael W Parker, Yan Yan, Karsten Melcher, Bruce E Kemp, Jonathan S Oakhill, Gregory R Steinberg. Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nature metabolism. 2020 Sep;2(9):873-881

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    PMID: 32719536

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