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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-oxidation2,3,4,5,6. 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.

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Fig. 1: LCFA-CoAs are direct AMPK activators.
Fig. 2: LCFA-CoA activation is mediated through the AMPK ADaM site.
Fig. 3: FA-CoAs increase fatty acid oxidation through AMPK phosphorylation of ACC.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon request. Source data for Figs. 13 and Extended Data Figs. 17 are available online.

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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. 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 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.

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S.L.P., J.W.S., E.M.D., B.K.S., E.A.D., R.J.F., C.G.L., N.X.Y.L., T.L.N., K.L., S.G., A.H., W.J.S., K.R.W.N. and Y.Y. performed the experiments. S.L.P., J.W.S., S.G., M.W.P., K.M., B.E.K., J.S.O. and G.R.S. provided intellectual input. S.L.P., B.E.K., J.S.O. and G.R.S. wrote the manuscript with contributions from all authors.

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Correspondence to Jonathan S. Oakhill or Gregory R. Steinberg.

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Extended data

Extended Data Fig. 1 Specificity of AMPK activation by palmitoyl-CoA and effects of co-incubations with free palmitate or coenzyme A.

a, b, Activities of AMPKα1β1γ1 (Sf9 insect cell-expressed), determined by TR-FRET SAMS assay, in the presence of coenzymes (100 µM), cofactors (100 µM) and vitamins (100 µM) (a), or following 15 min pre-incubation in the presence of palmitoyl-CoA (10 µM) ± indicated concentrations of free palmitate or coenzyme A (b). Data are shown as mean fold change in AMPK activity vs. vehicle ± s.e.m. For a, n = 3 except for folic acid, thiamine, riboflavin, pyridoxine, biotin and niacin (n = 2); for b, n = 5 (palmitate incubation) or n = 3 (coenzyme A incubation). Statistical significance was calculated using one-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments.

Source data

Extended Data Fig. 2 Palmitoyl-CoA activation of purified AMPK is sensitive to the method of protein immobilization.

a, b, Activities of AMPKα1β1γ1 (COS7 cell-expressed; fusion tags as indicated) were determined by 32P SAMS peptide assay ± palmitoyl-CoA (10 µM), A769662 (10 μM) or AMP (100 µM), following immobilization on anti-flag agarose (a) or glutathione-Sepharose (b). Data are shown as mean fold change in AMPK activity vs. vehicle ± s.e.m., n = 3. c, Activities of AMPKα1β1γ1 (COS7 cell-expressed; fusion tags as indicated) were determined by 32P SAMS peptide assay ± palmitoyl-CoA (10 µM), prepared in either H2O or 50 mM HEPES, following immobilization on anti-myc agarose. Data are shown as mean specific activity ± s.e.m., n = 3. Statistical significance was calculated using one-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments.

Source data

Extended Data Fig. 3 Characterization of LCFA-CoA activation of AMPK.

a, Activities of AMPKα1β1γ1 (COS7 cell-expressed, WT and β1S108A mutant) were determined by 32P SAMS assay, following immobilization on anti-myc agarose, ± palmitoyl-CoA, myristoyl-CoA or lauroyl-CoA (10 μM). Data are shown as mean fold change in AMPK activity vs. vehicle ± s.e.m., n=3. Statistical significance was calculated using two-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments. b, Activities of AMPKα1β1γ1 (Sf9 insect cell-expressed) were determined by TR-FRET in the presence of the indicated concentration of phosphatase PP2Cα ± AMP (30 µM) or palmitoyl-CoA (10 µM). Data are shown as mean fold change in AMPK activity vs. vehicle ± s.e.m., n=10 except for AMP incubated (n = 5). Statistical significance was calculated using two-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments. c, d, Binding of [3H]-palmitoyl-CoA to AMPKα1β1γ1 (E. coli-expressed) ± increasing concentrations of unlabeled palmitoyl-CoA (c), or to various AMPK preparations (d). GST-αRIM2: His6-GST-LVPRGS(thrombin cleavage site)-α1(282-374). Data are shown as mean relative binding ± s.e.m. For c, n = 2; for d, n = 3. Statistical significance was calculated using one-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments.

Source data

Extended Data Fig. 4 The channel at the interface between AMPK α2- and β1-subunits used for docking palmitoyl-CoA, interactions made by pSer108 and comparison with ADaM site activators.

(a) In the PDB ID:4CFF15 AMPK structure (shown as cartoon), the channel (that is the docking protomol, yellow molecular surface) encompasses the ADaM site (located directly above the ATP binding site of the α2-subunit kinase domain) and continues into a pocket located beneath the cyclodextran binding groove of the β1-CBM. In this AMPK structure, the channel is blocked at approximately the α-B helix of the α2-subunit by residues Arg49, Arg53, Pro86 and Thr87 of the α2-subunit and Pro140, Gln154, Lys156, Asp159 and Lys172 of the β1-subunit. Whereas in the (b) 5ISO56 and (c) 6B1U38 AMPK structures, the channel runs the full width across the α2- and β1-subunit interface (that is from the start of the ADaM site to the C-interacting helix of the β1-subunit, including the pocket beneath the cyclodextran binding groove of the β1-CBM). Polar interactions made by pSer108 in the (d) palmitoyl-CoA:AMPKα2β1γ1 model, (e) SC4:AMPKα2β1γ1 crystal structure (PDB ID: 6B1U) and (f) A-769662:AMPKα2β1γ1 crystal structure (PDB ID: 4CFF). (g) Overlay of the palmitoyl-CoA:AMPKα2β1γ1 model with the A-769662:AMPKα2β1γ1 and SC4:AMPKα2β1γ1 crystal structures (only A-769962 and SC4 shown for clarity). The same view is shown in panels a-c and d-g, the structures have been aligned via their β1-subunit CBM. In panels a-c, the location of the ATP binding site in the α2-subunit kinase domain is indicated by staurosporine (cyan sticks). Residues from the α2-catalytic subunit are underlined. Polar interactions are indicated by black dashed lines.

Extended Data Fig. 5 Unique palmitoyl-CoA conformation clusters consistent with our experimental data.

Docking into the (a) 4CFF, (b) 5ISO and (c) 6B1U active AMPKα2β1γ1 structures (grey cartoon). Palmitoyl-CoA shown as sticks, with the carbon atoms coloured either yellow or green. (d) Overlay of all docked palmitoyl-CoA poses except for those in Clusters 2, 4 and 5 for the 5ISO AMPK structure. The overlay shows that the different conformational clusters for the 4CFF, 5ISO and 6B1U AMPK structures fall under a general binding mode. Carbon, sulphur, nitrogen, oxygen and phosphorous atoms are coloured grey, yellow, blue, red and orange respectively.

Extended Data Fig. 6 Alignment of AMPK β1 and β2 sequences from diverse species.

Alignments to human AMPKβ1Gly86 and β2Glu85 residues are in bold.

Extended Data Fig. 7 AMPKβ1N111 does not alter sensitivity to palmitoyl-CoA or AMP.

AMPK activity of AMPKα1β1γ1 (WT, β1N111A or β1N111D) was determined by 32P SAMS assay, following immobilization on anti-myc agarose, ± palmitoyl-CoA (10 µM) or AMP (100 µM). Data are shown as mean fold change in activity vs. vehicle, ± s.e.m.; n = 3. Statistical significance was calculated using two-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments.

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Pinkosky, S.L., Scott, J.W., Desjardins, E.M. et al. Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nat Metab 2, 873–881 (2020). https://doi.org/10.1038/s42255-020-0245-2

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