1. Autophagy-mediated metabolic effects of aspirin
- Author
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Castoldi F., Humeau J., Martins I., Lachkar S., Loew D., Dingli F., Durand S., Enot D., Bossut N., Chery A., Aprahamian F., Demont Y., Opolon P., Signolle N., Sauvat A., Semeraro M., Bezu L., Baracco E. E., Vacchelli E., Pol J. G., Levesque S., Bloy N., Sica V., Maiuri M. C., Kroemer G., Pietrocola F., Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut Gustave Roussy (IGR), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Weill Medical College of Cornell University [New York], Universitat Pompeu Fabra [Barcelona] (UPF), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Castoldi, F., Humeau, J., Martins, I., Lachkar, S., Loew, D., Dingli, F., Durand, S., Enot, D., Bossut, N., Chery, A., Aprahamian, F., Demont, Y., Opolon, P., Signolle, N., Sauvat, A., Semeraro, M., Bezu, L., Baracco, E. E., Vacchelli, E., Pol, J. G., Levesque, S., Bloy, N., Sica, V., Maiuri, M. C., Kroemer, G., and Pietrocola, F.
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lcsh:Cytology ,[SDV]Life Sciences [q-bio] ,Macroautophagy ,Metabolic disorders ,lcsh:QH573-671 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Article - Abstract
International audience; Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b−/− or Bcln1+/−) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.
- Published
- 2020
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