Journal article

Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK beta 1 isoforms

Stephen L Pinkosky, John W Scott, Eric M Desjardins, Brennan K Smith, Emily A Day, Rebecca J Ford, Christopher G Langendorf, Naomi XY Ling, Tracy L Nero, Kim Loh, Sandra Galic, Ashfaqul Hoque, William J Smiles, Kevin RW Ngoei, Michael W Parker, Yan Yan, Karsten Melcher, Bruce E Kemp, Jonathan S Oakhill, Gregory R Steinberg

Nature Metabolism | NATURE RESEARCH | Published : 2020

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..

View full abstract

Grants

Awarded by Canadian Institutes of Health Research


Awarded by Diabetes Canada


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by Australian Research Council


Awarded by Jack Brockhoff Foundation


Awarded by National Institute of Health


Funding Acknowledgements

This work was supported by the Canadian Institutes of Health Research (no. 201709FDN-CEBA-116200 to G.R.S.), Diabetes Canada (no. DI-5-17-5302-GS) and project grants from the National Health and Medical Research Council of Australia (NHMRC; nos. 1098459 to J.S.O., J.W.S. and B.E.K.; 1145265 to J.S.O. and B.E.K.; 1085460 to B.E.K., S.G. and G.R.S.; 1138102 to J.W.S. and B.E.K.), the Australian Research Council (no. DP170101196 to B.E.K.), the Jack Brockhoff Foundation (no. JBF4206 to C.G.L.) and the Van Andel Research Institute and the National Institute of Health (no. R01 GM129436) to K.M. G.R.S. is supported by a Tier 1 Canada Research Chair and a J. Bruce Duncan Chair in Metabolic Diseases. B.E.K. and M.W.P. are NHMRC Fellows and C.G.L. is an NHMRC Early Career Research Fellow. This study was supported in part by the Victorian Government's Operational Infrastructure Support Programme.