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

doi:10.1038/s42255-020-0245-2

. 2020 Sep;2(9):873-881.

doi: 10.1038/s42255-020-0245-2. Epub 2020 Jul 27.

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

Stephen L Pinkosky^#¹, John W Scott^#^{2

3

4}, Eric M Desjardins¹, Brennan K Smith¹, Emily A Day¹, Rebecca J Ford¹, Christopher G Langendorf², Naomi X Y Ling⁵, Tracy L Nero^{6

7}, Kim Loh², Sandra Galic², Ashfaqul Hoque⁵, William J Smiles⁵, Kevin R W Ngoei², Michael W Parker^{6

7}, Yan Yan⁸, Karsten Melcher⁸, Bruce E Kemp^{2

3}, Jonathan S Oakhill^{9

10}, Gregory R Steinberg^{11

12}

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
PMCID: PMC7502547
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 et al. Nat Metab. 2020 Sep.

. 2020 Sep;2(9):873-881.

doi: 10.1038/s42255-020-0245-2. Epub 2020 Jul 27.

Authors

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
PMCID: PMC7502547
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-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.

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Figures

**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.

**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.

**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.

**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:4CFF AMPK structure (shown as cartoon), the channel (*i.e.* 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)** 5ISO and **(c)** 6B1U AMPK structures, the channel runs the full width across the α2- and β1-subunit interface (*i.e.* 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.

**Figure 1.. LCFA-CoAs are direct AMPK activators.**
a, Structures of LCFAs (*upper*) and LCFA-CoAs (*lower*). **b-e**, Activities of AMPKα1β1γ1 (Sf9 insect cell-expressed), determined by TR-FRET SAMS assay, in the presence of increasing concentrations of myristate, palmitate, their respective CoA thioester conjugates and AMP (b), acyl-CoA esters (10 μM) with chain lengths ranging from C2 to C18 (c), metabolites or biosynthetic precursors important for palmitoyl-CoA synthesis or catabolism (d) or ± 10 μM palmitoyl-CoA and the indicated concentrations of AMP (e). Data are shown as mean fold change in activity vs. vehicle ± s.e.m. For b, n = 2; for c, n = 7 except for propionyl-, butyryl-, hexanoyl- and oleoyl-CoAs (n =8) and acetyl-CoA (n = 3); for d, n = 3 except for pantothenic acid (n = 2); for e, n = 6. Statistical significance was calculated using one-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments. **f-h,** Activities of AMPK complexes (COS7 cell-expressed; basal activities detailed in Extended Data Table 1), determined by ³²P SAMS peptide assay following anti-myc agarose immobilization, of α1 and α2 AMPK ± palmitoyl-CoA (10 μM), A769662 (10 μM) or AMP (100 μM) (f), γ1 mutants ± AMP (100 μM) or palmitoyl-CoA (10 μM) (g) and β1 and β2 AMPK ± palmitoyl-CoA (10 μM), A769662 (10 μM) or AMP (100 μM) (h). For f, h, data are shown as mean fold change in activity vs. vehicle ± s.e.m.; n = 3. For g, data are shown as mean specific activity ± s.e.m.; n = 4. Statistical significance was calculated using two-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments. Immunoblot shows relative expression of flag-AMPK in COS7 cells. (i) Activities of purified AMPK complexes α1β1γ1 and α1β2γ1 (*E. coli*-expressed; basal activities detailed in Extended Data Table 2), determined by ³²P SAMS peptide assay, ± 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.

**Figure 2.. LCFA-CoA activation is mediated through the AMPK ADaM site.**
a, Activities of AMPKα1β1γ1 (WT or N-terminal deletions of β1 residues 1-71 (Δ71) or 1-145 (Δ145)) ± palmitoyl-CoA (10 μM) or AMP (100 μM). b, c, Activities of AMPKα1β1γ1 (WT or β1S108A) ± palmitoyl-CoA (10 μM) or AMP (100 μM) (b) or increasing concentration of palmitoyl-CoA (c). For a, b, data are shown as mean fold change in activity vs. vehicle ± s.e.m.; n = 3. For c, data are shown as mean specific activity ± s.e.m.; n = 3. Statistical significance was calculated using two-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments. d, *In silico* modelling of palmitoyl-CoA bound to AMPKα2β1γ1. e, f, Activities of AMPKα1β1γ1 and α2β1γ1 (WT or β1G86E) (e), or AMPK α1β2γ1 and α2β2γ1 (WT or β2E85G) (f) ± palmitoyl-CoA (10 μM), A769662 (10 μM) or AMP (100 μM). Data are shown as mean specific activity ± s.e.m.; n = 3. Statistical significance was calculated using two-way ANOVA with Bonferroni’s multiple comparisons test, or unpaired, 2-tailed Student’s t test (red P values). n represent biological independent experiments. Activities determined by ³²P SAMS peptide assay. COS7 cell-expressed AMPK immobilized on anti-myc agarose was used in all experiments unless indicated.

**Figure 3.. FA-CoAs increase fatty acid oxidation through AMPK phosphorylation of ACC.**
a, Primary mouse hepatocytes from C57Bl6J mice were treated with vehicle or palmitate (100, 250, or 500 μM) followed by western blotting for total AMPKα, phosphorylated-AMPK (p-AMPK, α-Thr172), total ACC, phosphorylated-ACC (p-ACC, Ser79/212) and β-actin. Data are shown as mean fold change in phosphorylation of AMPK (n = 5) or ACC (n = 6) vs. vehicle ± s.e.m. b, Primary mouse hepatocytes from C57Bl6J mice were treated with vehicle or 500 μM palmitate, bromo-palmitate (Br-Palmitate) or methyl-palmitate (Me-Palmitate) followed by western blotting for total ACC, phosphorylated-ACC (p-ACC, Ser79/212) and β-actin. Data are shown as mean fold change in phosphorylation of ACC (n = 6) vs. vehicle ± s.e.m. Statistical significance was calculated using one-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments. Representative immunoblots are shown. c, Respiratory Exchange Ratios (R.E.R.) of WT and ACC DKI mice following oral administration of saline (Veh), or Intralipid® (10 ml/kg). Data are shown as mean R.E.R. ± s.e.m. (WT, n = 7; ACC DKI, n = 8). Statistical significance was calculated using two-way ANOVA with Bonferroni’s multiple comparisons test. n represent biological independent experiments. **d-f**, WT and ACC DKI mice, following oral administration of saline (Vehicle) or Intralipid® (10 ml/kg), were measured for lipid oxidation rates calculated from R.E.R. over 4 h, starting 1 h post-gavage (d), food intake during 2 h re-feed (e) and activity levels 6 h post-gavage (f). Data are shown as mean fold change in lipid oxidation rate vs. vehicle (d), mean food intake (e) and mean total beam breaks (f) ± s.e.m. (WT, n = 7; ACC DKI, n = 8). Statistical significance was calculated using unpaired, 2-tailed Student’s t test with Bonferroni’s multiple comparisons test. n represent biological independent experiments.

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References

1. Faergeman NJ & Knudsen J Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. Biochem J 323 ( Pt 1), 1–12 (1997). - PMC - PubMed
1. Bortz WM & Lynen F THE INHIBITION OF ACETYL COA CARBOXYLASE BY LONG CHAIN ACYL COA DERIVATIVES. Biochem Z 337, 505–509 (1963). - PubMed
1. McGarry JD & Foster DW In support of the roles of malonyl-CoA and carnitine acyltransferase I in the regulation of hepatic fatty acid oxidation and ketogenesis. J Biol Chem 254, 8163–8168 (1979). - PubMed
1. McGarry JD, Takabayashi Y & Foster DW The role of malonyl-coa in the coordination of fatty acid synthesis and oxidation in isolated rat hepatocytes. J Biol Chem 253, 8294–8300 (1978). - PubMed
1. Trumble GE, Smith MA & Winder WW Purification and characterization of rat skeletal muscle acetyl-CoA carboxylase. Eur J Biochem 231, 192–198, doi:10.1111/j.1432-1033.1995.tb20686.x (1995). - DOI - PubMed

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[1] Faergeman NJ & Knudsen J Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. Biochem J 323 ( Pt 1), 1–12 (1997). - PMC - PubMed

[2] Faergeman NJ & Knudsen J Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. Biochem J 323 ( Pt 1), 1–12 (1997). - PMC - PubMed

[3] Bortz WM & Lynen F THE INHIBITION OF ACETYL COA CARBOXYLASE BY LONG CHAIN ACYL COA DERIVATIVES. Biochem Z 337, 505–509 (1963). - PubMed

[4] Bortz WM & Lynen F THE INHIBITION OF ACETYL COA CARBOXYLASE BY LONG CHAIN ACYL COA DERIVATIVES. Biochem Z 337, 505–509 (1963). - PubMed

[5] McGarry JD & Foster DW In support of the roles of malonyl-CoA and carnitine acyltransferase I in the regulation of hepatic fatty acid oxidation and ketogenesis. J Biol Chem 254, 8163–8168 (1979). - PubMed

[6] McGarry JD & Foster DW In support of the roles of malonyl-CoA and carnitine acyltransferase I in the regulation of hepatic fatty acid oxidation and ketogenesis. J Biol Chem 254, 8163–8168 (1979). - PubMed

[7] McGarry JD, Takabayashi Y & Foster DW The role of malonyl-coa in the coordination of fatty acid synthesis and oxidation in isolated rat hepatocytes. J Biol Chem 253, 8294–8300 (1978). - PubMed

[8] McGarry JD, Takabayashi Y & Foster DW The role of malonyl-coa in the coordination of fatty acid synthesis and oxidation in isolated rat hepatocytes. J Biol Chem 253, 8294–8300 (1978). - PubMed

[9] Trumble GE, Smith MA & Winder WW Purification and characterization of rat skeletal muscle acetyl-CoA carboxylase. Eur J Biochem 231, 192–198, doi:10.1111/j.1432-1033.1995.tb20686.x (1995). - DOI - PubMed

[10] Trumble GE, Smith MA & Winder WW Purification and characterization of rat skeletal muscle acetyl-CoA carboxylase. Eur J Biochem 231, 192–198, doi:10.1111/j.1432-1033.1995.tb20686.x (1995). - DOI - PubMed

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

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

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