Chronic High Fat Feeding Restricts Islet mRNA Translation Initiation Independently of ER Stress Via DNA Damage and p53 Activation

Presentation Number: SUN 602
Date of Presentation: April 2nd, 2017

Masayuki Hatanaka1, Emily Anderson-baucum2, Alexander Lakhter2, Tatsuyoshi Kono3, Yukio Tanizawa4, Carmella Evans-Molina5, Raghavendra G Mirmira6 and Emily Kristen Sims*7
1Yamaguchi University Graduate School of Medicine, 2Indiana University School of Medicine, 3Indiana University, 4Yamaguchi University Graduate School of Medicine, Ube Yamaguchi, Japan, 5Indiana University School of Medicine, Indianapolis, IN, 6Indiana Univ Sch of Medicine, Indianapolis, IN, 7Indiana University Scool of Medicine, Indianapolis, IN

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 profiling analysis of islets from mice fed 16-weeks of 42% HFD compared to regular chow. HFD-islet analysis revealed clear trends toward global reductions in mRNA translation. A significant reduction in the polyribosome/monoribosome ratio was present for Pdx1 mRNA, consistent with reduced translation initiation. Transcriptional and translational analyses revealed endoplasmic reticulum stress was not the etiology of our findings. HFD-islets demonstrated accumulation of reactive nitrogen species and DNA damage, as well as activation of p53, an established regulator of global mRNA translation. Experiments in MIN-6 β-cells revealed that treatment with doxorubicin to directly induce DNA damage and p53 activation mimicked our observed effects in islets. Islets from animals treated with pioglitazone concurrently with HFD demonstrated a reversal of effects observed from HFD alone. We propose a heretofore unappreciated β-cell effect of chronic HFD, wherein continued DNA damage due to persistent oxidative stress results in p53 activation and a resultant inhibition of mRNA translation.

 

Nothing to Disclose: MH, EA, AL, TK, YT, CE, RGM, EKS