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; Gregory R. Steinberg

doi:10.1038/s42255-020-0245-2

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, Gregory R. Steinberg

Research output: Contribution to journal › Article › Research › peer-review

111 Citations (Scopus)

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-oxidation^2–6. 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.

Original language	English
Pages (from-to)	873-881
Number of pages	9
Journal	Nature Metabolism
Volume	2
Issue number	9
DOIs	https://doi.org/10.1038/s42255-020-0245-2
Publication status	Published - 1 Sept 2020
Externally published	Yes

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Pinkosky, S. L., Scott, J. W., Desjardins, E. M., Smith, B. K., Day, E. A., Ford, R. J., Langendorf, C. G., Ling, N. X. Y., Nero, T. L., Loh, K., Galic, S., Hoque, A., Smiles, W. J., Ngoei, K. R. W., Parker, M. W., Yan, Y., Melcher, K., Kemp, B. E., Oakhill, J. S., & Steinberg, G. R. (2020). Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nature Metabolism, 2(9), 873-881. https://doi.org/10.1038/s42255-020-0245-2

@article{698e124a715e47e88f19b2a57d03e917,

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

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.",

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

note = "Funding Information: 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. JBF-4206 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 Tier1 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{\textquoteright}s Operational Infrastructure Support Programme. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = sep,

day = "1",

doi = "10.1038/s42255-020-0245-2",

language = "English",

volume = "2",

pages = "873--881",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Nature Publishing Group",

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Pinkosky, SL, Scott, JW, Desjardins, EM, Smith, BK, Day, EA, Ford, RJ, Langendorf, CG, Ling, NXY, Nero, TL, Loh, K, Galic, S, Hoque, A, Smiles, WJ, Ngoei, KRW, Parker, MW, Yan, Y, Melcher, K, Kemp, BE, Oakhill, JS & Steinberg, GR 2020, 'Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms', Nature Metabolism, vol. 2, no. 9, pp. 873-881. https://doi.org/10.1038/s42255-020-0245-2

TY - JOUR

T1 - Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms

AU - Pinkosky, Stephen L.

AU - Scott, John W.

AU - Desjardins, Eric M.

AU - Smith, Brennan K.

AU - Day, Emily A.

AU - Ford, Rebecca J.

AU - Langendorf, Christopher G.

AU - Ling, Naomi X.Y.

AU - Nero, Tracy L.

AU - Loh, Kim

AU - Galic, Sandra

AU - Hoque, Ashfaqul

AU - Smiles, William J.

AU - Ngoei, Kevin R.W.

AU - Parker, Michael W.

AU - Yan, Yan

AU - Melcher, Karsten

AU - Kemp, Bruce E.

AU - Oakhill, Jonathan S.

AU - Steinberg, Gregory R.

N1 - Funding Information: 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. JBF-4206 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 Tier1 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. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85088600360&partnerID=8YFLogxK

U2 - 10.1038/s42255-020-0245-2

DO - 10.1038/s42255-020-0245-2

M3 - Article

C2 - 32719536

AN - SCOPUS:85088600360

SN - 2522-5812

VL - 2

SP - 873

EP - 881

JO - Nature Metabolism

JF - Nature Metabolism

IS - 9

ER -

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

Abstract

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