Palmitate Induces mRNA Translation and Increases ER Protein Load in Islet β Cells via Activation of the Mammalian Target of Rapamycin Pathway

  1. Raghavendra G. Mirmira1,2,3,5,6
  1. 1Department of Pediatrics,
  2. 2Herman B Wells Center for Pediatric Research,
  3. 3Department of Cellular and Integrative Physiology,
  4. 5Department of Medicine, and
  5. 6Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
  6. 4Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA
  1. Corresponding author: Raghavendra G. Mirmira, E-mail: rmirmira{at}iu.edu.

Abstract

Saturated free fatty acids have complex effects on the islet β cell, acutely promoting adaptive hyperplasia, but chronically impairing insulin release. The acute effects of free fatty acids remain incompletely defined. To elucidate these early molecular events, we incubated mouse β cells and islets with palmitate, then studied mRNA translation by polyribosomal profiling and analyzed signaling pathways by immunoblot analysis. We found that palmitate acutely increases polyribosome occupancy of total RNA, consistent with an increase in mRNA translation. This effect on translation was attributable to activation of mTOR pathways via L-type Ca2+ channels, but was independent of insulin signaling. Longer incubations led to depletion of polyribosome-associated RNA, consistent with activation of the unfolded protein response. Pharmacologic inhibition of mTOR suppressed both the acute effects of palmitate on mRNA translation and the chronic effects on the unfolded protein response. Islets from mice fed a high fat diet for 7 days showed increases in polyribosome-associated RNA and phosphorylation of S6K, both consistent with activation of mTOR. Our results suggest that palmitate acutely activates mRNA translation, and that this increase in protein load contributes to the later unfolded protein response.

  • Received January 20, 2014.
  • Accepted May 6, 2014.

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