Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation

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...

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Autores principales:	Masayuki Hatanaka, Emily Anderson-Baucum, Alexander Lakhter, Tatsuyoshi Kono, Bernhard Maier, Sarah A. Tersey, Yukio Tanizawa, Carmella Evans-Molina, Raghavendra G. Mirmira, Emily K. Sims
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/55e51cc8fc5a42f3821a8cee071ffc18
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spelling	oai:doaj.org-article:55e51cc8fc5a42f3821a8cee071ffc182021-12-02T16:06:06ZChronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation10.1038/s41598-017-03869-52045-2322https://doaj.org/article/55e51cc8fc5a42f3821a8cee071ffc182017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03869-5https://doaj.org/toc/2045-2322Abstract 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.Masayuki HatanakaEmily Anderson-BaucumAlexander LakhterTatsuyoshi KonoBernhard MaierSarah A. TerseyYukio TanizawaCarmella Evans-MolinaRaghavendra G. MirmiraEmily K. SimsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Masayuki Hatanaka Emily Anderson-Baucum Alexander Lakhter Tatsuyoshi Kono Bernhard Maier Sarah A. Tersey Yukio Tanizawa Carmella Evans-Molina Raghavendra G. Mirmira Emily K. Sims Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
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.
format	article
author	Masayuki Hatanaka Emily Anderson-Baucum Alexander Lakhter Tatsuyoshi Kono Bernhard Maier Sarah A. Tersey Yukio Tanizawa Carmella Evans-Molina Raghavendra G. Mirmira Emily K. Sims
author_facet	Masayuki Hatanaka Emily Anderson-Baucum Alexander Lakhter Tatsuyoshi Kono Bernhard Maier Sarah A. Tersey Yukio Tanizawa Carmella Evans-Molina Raghavendra G. Mirmira Emily K. Sims
author_sort	Masayuki Hatanaka
title	Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
title_short	Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
title_full	Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
title_fullStr	Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
title_full_unstemmed	Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
title_sort	chronic high fat feeding restricts islet mrna translation initiation independently of er stress via dna damage and p53 activation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/55e51cc8fc5a42f3821a8cee071ffc18
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Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation

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