Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis
| Autor: | Debra L. Robson, Nica M. Borradaile, Alexandra M. Stoianov, Cynthia G. Sawyez, Alexandra M. Hetherington |
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| Rok vydání: | 2015 |
| Předmět: |
Leptin
Male medicine.medical_specialty Programmed cell death Palmitates Peptide Chain Elongation Translational lcsh:Medicine Mice Obese Apoptosis Biology Endoplasmic Reticulum Didemnin B Mice Peptide Elongation Factor 1 Dietary Sucrose Non-alcoholic Fatty Liver Disease Internal medicine Depsipeptides medicine Animals Humans lcsh:Science Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins Multidisciplinary Endoplasmic reticulum lcsh:R Hep G2 Cells Actin cytoskeleton Endoplasmic Reticulum Stress Dietary Fats Transport protein Elongation factor Mice Inbred C57BL Protein Transport Endocrinology Lipotoxicity Gene Expression Regulation Models Animal Unfolded protein response Hepatocytes lcsh:Q Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 10, Iss 6, p e0131269 (2015) |
| ISSN: | 1932-6203 |
| Popis: | Elongation factor 1A-1 (eEF1A-1) has non-canonical functions in regulation of the actin cytoskeleton and apoptosis. It was previously identified through a promoter-trap screen as a mediator of fatty acid-induced cell death (lipotoxicity), and was found to participate in this process downstream of ER stress. Since ER stress is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), we investigated the mechanism of action of eEF1A-1 in hepatocyte lipotoxicity. HepG2 cells were exposed to excess fatty acids, followed by assessments of ER stress, subcellular localization of eEF1A-1, and cell death. A specific inhibitor of eEF1A-1 elongation activity, didemnin B, was used to determine whether its function in protein synthesis is involved in lipotoxicity. Within 6 h, eEF1A-1 protein was modestly induced by high palmitate, and partially re-localized from its predominant location at the ER to polymerized actin at the cell periphery. This early induction and subcellular redistribution of eEF1A-1 coincided with the onset of ER stress, and was later followed by cell death. Didemnin B did not prevent the initiation of ER stress by high palmitate, as indicated by eIF2α phosphorylation. However, consistent with sustained inhibition of eEF1A-1-dependent elongation activity, didemnin B prevented the recovery of protein synthesis and increase in GRP78 protein that are normally associated with later phases of the response to ongoing ER stress. This resulted in decreased palmitate-induced cell death. Our data implicate eEF1A-1, and its function in protein synthesis, in hepatocyte lipotoxicity. |
| Databáze: | OpenAIRE |
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