Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
dc.contributor.author | Hatanaka, Masayuki | |
dc.contributor.author | Anderson-Baucum, Emily | |
dc.contributor.author | Lakhter, Alexander | |
dc.contributor.author | Kono, Tatsuyoshi | |
dc.contributor.author | Maier, Bernhard | |
dc.contributor.author | Tersey, Sarah A. | |
dc.contributor.author | Tanizawa, Yukio | |
dc.contributor.author | Evans-Molina, Carmella | |
dc.contributor.author | Mirmira, Raghavendra G. | |
dc.contributor.author | Sims, Emily K. | |
dc.contributor.department | Pediatrics, School of Medicine | en_US |
dc.date.accessioned | 2017-11-16T21:14:23Z | |
dc.date.available | 2017-11-16T21:14:23Z | |
dc.date.issued | 2017-06-19 | |
dc.description.abstract | Under conditions of high fat diet (HFD) consumption, glucose dyshomeostasis develops when β-cells are unable to adapt to peripheral insulin demands. Few studies have interrogated the molecular mechanisms of β-cell dysfunction at the level of mRNA translation under such conditions. We sought to address this issue through polyribosome profile analysis of islets from mice fed 16-weeks of 42% HFD. HFD-islet analysis revealed clear trends toward global reductions in mRNA translation with a significant reduction in the polyribosome/monoribosome ratio for Pdx1 mRNA. Transcriptional and translational analyses revealed endoplasmic reticulum stress was not the etiology of our findings. HFD-islets demonstrated evidence of oxidative stress and DNA damage, as well as activation of p53. Experiments in MIN-6 β-cells revealed that treatment with doxorubicin to directly induce DNA damage mimicked our observed effects in islets. Islets from animals treated with pioglitazone concurrently with HFD demonstrated a reversal of effects observed from HFD alone. Finally, HFD-islets demonstrated reduced expression of multiple ribosome biogenesis genes and the key translation initiation factor eIF4E. We propose a heretofore unappreciated effect of chronic HFD on β-cells, wherein continued DNA damage owing to persistent oxidative stress results in p53 activation and a resultant inhibition of mRNA translation. | en_US |
dc.eprint.version | Final published version | |
dc.identifier.citation | Hatanaka, M., Anderson-Baucum, E., Lakhter, A., Kono, T., Maier, B., Tersey, S. A., … Sims, E. K. (2017). Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation. Scientific Reports, 7, 3758. http://doi.org/10.1038/s41598-017-03869-5 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/14575 | |
dc.language.iso | en_US | en_US |
dc.publisher | Springer Nature | en_US |
dc.relation.isversionof | 10.1038/s41598-017-03869-5 | en_US |
dc.relation.journal | Scientific Reports | en_US |
dc.rights | Attribution 3.0 United States | |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | |
dc.source | PMC | en_US |
dc.subject | DNA damage response | en_US |
dc.subject | Translation | en_US |
dc.subject | Type 2 diabetes | en_US |
dc.title | Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation | en_US |
dc.type | Article | en_US |
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