Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis.
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...
Main Authors: | , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2015-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4478042?pdf=render |
id |
doaj-bcb5f74d543d4e1db84f95f56925ccc0 |
---|---|
record_format |
Article |
spelling |
doaj-bcb5f74d543d4e1db84f95f56925ccc02020-11-25T01:23:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01106e013126910.1371/journal.pone.0131269Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis.Alexandra M StoianovDebra L RobsonAlexandra M HetheringtonCynthia G SawyezNica M BorradaileElongation 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.http://europepmc.org/articles/PMC4478042?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alexandra M Stoianov Debra L Robson Alexandra M Hetherington Cynthia G Sawyez Nica M Borradaile |
spellingShingle |
Alexandra M Stoianov Debra L Robson Alexandra M Hetherington Cynthia G Sawyez Nica M Borradaile Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. PLoS ONE |
author_facet |
Alexandra M Stoianov Debra L Robson Alexandra M Hetherington Cynthia G Sawyez Nica M Borradaile |
author_sort |
Alexandra M Stoianov |
title |
Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. |
title_short |
Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. |
title_full |
Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. |
title_fullStr |
Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. |
title_full_unstemmed |
Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. |
title_sort |
elongation factor 1a-1 is a mediator of hepatocyte lipotoxicity partly through its canonical function in protein synthesis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4478042?pdf=render |
work_keys_str_mv |
AT alexandramstoianov elongationfactor1a1isamediatorofhepatocytelipotoxicitypartlythroughitscanonicalfunctioninproteinsynthesis AT debralrobson elongationfactor1a1isamediatorofhepatocytelipotoxicitypartlythroughitscanonicalfunctioninproteinsynthesis AT alexandramhetherington elongationfactor1a1isamediatorofhepatocytelipotoxicitypartlythroughitscanonicalfunctioninproteinsynthesis AT cynthiagsawyez elongationfactor1a1isamediatorofhepatocytelipotoxicitypartlythroughitscanonicalfunctioninproteinsynthesis AT nicamborradaile elongationfactor1a1isamediatorofhepatocytelipotoxicitypartlythroughitscanonicalfunctioninproteinsynthesis |
_version_ |
1725120775096107008 |