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

  • Nat Metab. 2020 Sep;2(9):873-881. doi: 10.1038/s42255-020-0245-2.
Stephen L Pinkosky  #  1 ,  John W Scott  #  2  3  4 ,  Eric M Desjardins  1 ,  Brennan K Smith  1 ,  Emily A Day  1 ,  Rebecca J Ford  1 ,  Christopher G Langendorf  2 ,  Naomi X Y Ling  5 ,  Tracy L Nero  6  7 ,  Kim Loh  2 ,  Sandra Galic  2 ,  Ashfaqul Hoque  5 ,  William J Smiles  5 ,  Kevin R W Ngoei  2 ,  Michael W Parker  6  7 ,  Yan Yan  8 ,  Karsten Melcher  8 ,  Bruce E Kemp  2  3 ,  Jonathan S Oakhill  9  10 ,  Gregory R Steinberg  11  12
Affiliations
  • 1. Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
  • 2. Protein Chemistry & Metabolism, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia.
  • 3. Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, Victoria, Australia.
  • 4. The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
  • 5. Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia.
  • 6. ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia.
  • 7. Structural Biology and Computational Design Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
  • 8. Center for Cancer and Cell Biology, Structural Biology Program, Van Andel Research Institute, Grand Rapids, MI, USA.
  • 9. Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, Victoria, Australia. [email protected].
  • 10. Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia. [email protected].
  • 11. Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada. [email protected].
  • 12. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. [email protected].
  • # Contributed equally.
PMID: 32719536 DOI: 10.1038/s42255-020-0245-2
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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