Activation of the eIF2α-ATF4 Pathway by Chronic Paracetamol Treatment Is Prevented by Dietary Supplementation with Cysteine
| Autor: | Valérie Carraro, Lydie Combaret, Cécile Coudy-Gandilhon, Laurent Parry, Julien Averous, Anne-Catherine Maurin, Céline Jousse, Guillaume Voyard, Pierre Fafournoux, Isabelle Papet, Alain Bruhat |
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| Přispěvatelé: | Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Université Clermont Auvergne (UCA), Institut de Chimie de Clermont-Ferrand (ICCF), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Mammals
acetaminophen eIF2α-ATF4 pathway GCN2 cysteine liver skeletal muscle CARE-LUC mice Eukaryotic Initiation Factor-2 Organic Chemistry General Medicine Activating Transcription Factor 4 Glutathione Catalysis Computer Science Applications Inorganic Chemistry Muscular Atrophy eIF-2 Kinase Dietary Supplements Animals Cysteine Phosphorylation Physical and Theoretical Chemistry [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Molecular Biology [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition Spectroscopy Acetaminophen |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, 2022, 23 (13), pp.7196. ⟨10.3390/ijms23137196⟩ International Journal of Molecular Sciences; Volume 23; Issue 13; Pages: 7196 |
| ISSN: | 1661-6596 1422-0067 |
| DOI: | 10.3390/ijms23137196⟩ |
| Popis: | Chronic treatment with acetaminophen (APAP) induces cysteine (Cys) and glutathione (GSH) deficiency which leads to adverse metabolic effects including muscle atrophy. Mammalian cells respond to essential amino acid deprivation through the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Phosphorylated eIF2α leads to the recruitment of activating transcription factor 4 (ATF4) to specific CCAAT/enhancer-binding protein-ATF response element (CARE) located in the promoters of target genes. Our purpose was to study the activation of the eIF2α-ATF4 pathway in response to APAP-induced Cys deficiency, as well as the potential contribution of the eIF2α kinase GCN2 and the effect of dietary supplementation with Cys. Our results showed that chronic treatment with APAP activated both GCN2 and PERK eIF2α kinases and downstream target genes in the liver. Activation of the eIF2α-ATF4 pathway in skeletal muscle was accompanied by muscle atrophy even in the absence of GCN2. The dietary supplementation with cysteine reversed APAP-induced decreases in plasma-free Cys, liver GSH, muscle mass, and muscle GSH. Our new findings demonstrate that dietary Cys supplementation also reversed the APAP-induced activation of GCN2 and PERK and downstream ATF4-target genes in the liver. |
| Databáze: | OpenAIRE |
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