Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms
Journal article
Pinkosky, Stephen L., Scott, John W., Desjardins, Eric M., Smith, Brennan K., Day, Emily A., Ford, Rebecca J., Langendorf, Christopher G., Ling, Naomi X. Y., Nero, Tracy L., Loh, Kim, Galic, Sandra, Hoque, Ashfaqul, Smiles, William J., Ngoei, Kevin R. W., Parker, Michael W., Yan, Yan, Melcher, Karsten, Kemp, Bruce E., Oakhill, Jonathan S. and Steinberg, Gregory R.. (2020). Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nature Metabolism. 2(9), pp. 873-881. https://doi.org/10.1038/s42255-020-0245-2
Authors | Pinkosky, Stephen L., Scott, John W., Desjardins, Eric M., Smith, Brennan K., Day, Emily A., Ford, Rebecca J., Langendorf, Christopher G., Ling, Naomi X. Y., Nero, Tracy L., Loh, Kim, Galic, Sandra, Hoque, Ashfaqul, Smiles, William J., Ngoei, Kevin R. W., Parker, Michael W., Yan, Yan, Melcher, Karsten, Kemp, Bruce E., Oakhill, Jonathan S. and Steinberg, Gregory R. |
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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-oxidation2,3,4,5,6. 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. |
Year | 2020 |
Journal | Nature Metabolism |
Journal citation | 2 (9), pp. 873-881 |
Publisher | Nature Publishing Group |
ISSN | 2522-5812 |
Digital Object Identifier (DOI) | https://doi.org/10.1038/s42255-020-0245-2 |
PubMed ID | 32719536 |
Scopus EID | 2-s2.0-85088600360 |
PubMed Central ID | PMC7502547 |
Open access | Published as green open access |
Page range | 873-881 |
Funder | Department of Health and Human Services, Victoria |
Commonwealth Specialist Training Program | |
Australian National University (ANU) | |
Author's accepted manuscript | License All rights reserved File Access Level Open |
Publisher's version | License All rights reserved File Access Level Controlled |
Output status | Published |
Publication dates | |
Online | 27 Jul 2020 |
Publication process dates | |
Accepted | 11 May 2020 |
Deposited | 19 Apr 2021 |
https://acuresearchbank.acu.edu.au/item/8vx46/long-chain-fatty-acyl-coa-esters-regulate-metabolism-via-allosteric-control-of-ampk-1-isoforms
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File access level: Open |
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