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Laudette M, Sainte-Marie Y, Cousin G, et al. Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity. Cell Death Dis. 2021;12(9):824doi: 10.1038/s41419-021-04113-9.
Laudette, M., Sainte-Marie, Y., Cousin, G., Bergonnier, D., Belhabib, I., Brun, S., Formoso, K., Laib, L., Tortosa, F., Bergoglio, C., Marcheix, B., Borén, J., Lairez, O., Fauconnier, J., Lucas, A., Mialet-Perez, J., Moro, C., & Lezoualc'h, F. (2021). Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity. Cell death & disease, 12(9), 824. https://doi.org/10.1038/s41419-021-04113-9
Laudette, Marion, et al. "Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity." Cell death & disease vol. 12,9 (2021): 824. doi: https://doi.org/10.1038/s41419-021-04113-9
Laudette M, Sainte-Marie Y, Cousin G, Bergonnier D, Belhabib I, Brun S, Formoso K, Laib L, Tortosa F, Bergoglio C, Marcheix B, Borén J, Lairez O, Fauconnier J, Lucas A, Mialet-Perez J, Moro C, Lezoualc'h F. Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity. Cell Death Dis. 2021 Sep 01;12(9):824. doi: 10.1038/s41419-021-04113-9. PMID: 34471096; PMCID: PMC8410846.
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Cell Death Dis. 2021 Sep 01;12(9):824. doi: 10.1038/s41419-021-04113-9.

Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity.

Cell death & disease

Marion Laudette, Yannis Sainte-Marie, Grégoire Cousin, Dorian Bergonnier, Ismahane Belhabib, Stéphanie Brun, Karina Formoso, Loubna Laib, Florence Tortosa, Camille Bergoglio, Bertrand Marcheix, Jan Borén, Olivier Lairez, Jérémy Fauconnier, Alexandre Lucas, Jeanne Mialet-Perez, Cédric Moro, Frank Lezoualc'h

Affiliations

  1. Institut des Maladies Métaboliques et Cardiovasculaires, Inserm, Université Paul Sabatier, UMR 1297-I2MC, Toulouse, France.
  2. Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
  3. Centre Hospitalier Universitaire de Toulouse Rangueil, Toulouse, France.
  4. PHYMEDEXP, Université de Montpellier, CNRS, INSERM, CHRU Montpellier, Montpellier, France.
  5. Institut des Maladies Métaboliques et Cardiovasculaires, Inserm, Université Paul Sabatier, UMR 1297-I2MC, Toulouse, France. [email protected].

PMID: 34471096 PMCID: PMC8410846 DOI: 10.1038/s41419-021-04113-9

Abstract

Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cyclase in cardiomyocytes. cAMP further induced exchange protein directly activated by cyclic AMP 1 (Epac1) activation, which was upregulated in the myocardium of obese patients. Epac1 enhanced the activity of a key enzyme regulating mitochondrial FA uptake, carnitine palmitoyltransferase 1. Consistently, pharmacological or genetic Epac1 inhibition prevented lipid overload, increased FA oxidation (FAO), and protected against mitochondrial dysfunction in cardiomyocytes. In addition, analysis of Epac1 phosphoproteome led us to identify two key mitochondrial enzymes of the the β-oxidation cycle as targets of Epac1, the long-chain FA acyl-CoA dehydrogenase (ACADL) and the 3-ketoacyl-CoA thiolase (3-KAT). Epac1 formed molecular complexes with the Ca

© 2021. The Author(s).

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