2. Academic Validation
  3. Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

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

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. joakhill@svi.edu.au.
  • 10 Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Fitzroy, Victoria, Australia. joakhill@svi.edu.au.
  • 11 Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada. gsteinberg@mcmaster.ca.
  • 12 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. gsteinberg@mcmaster.ca.
  • # 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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