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2020

Nat Metab. 2020 Sep;2(9):873-881. doi: 10.1038/s42255-020-0245-2. Epub 2020 Jul 27.

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

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, and Gregory R. Steinberg.

Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Protein Chemistry & Metabolism, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia. Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, Victoria, Australia. The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia. Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia. ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia. Structural Biology and Computational Design Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia. Center for Cancer and Cell Biology, Structural Biology Program, Van Andel Research Institute, Grand Rapids, MI, USA. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. 

Service type: Knockout mice

Abstract

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.

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