Palmitate induces mRNA translation and increases ER protein load in islet ß-cells via activation of the mammalian target of rapamycin pathway

Masayuki Hatanaka, Bernhard Maier, Emily K. Sims, Andrew T. Templin, Rohit N. Kulkarni, Carmella Evans-Molina, Raghu Mirmira

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Saturated free fatty acids (FFAs) have complex effects on the islet ß-cell, acutely promoting adaptive hyperplasia but chronically impairing insulin release. The acute effects of FFAs remain incompletely defined. To elucidate these early molecular events, we incubated mouse ß-cells and islets with palmitate and 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 mammalian target of rapamycin (mTOR) pathways via L-type Ca<sup>2+</sup>channels but was independent of insulin signaling. Longer incubations led to depletion of polyribosome-associated RNA, consistent with activation of the unfolded protein response (UPR). Pharmacologic inhibition of mTOR suppressed both the acute effects of palmitate on mRNA translation and the chronic effects on the UPR. Islets from mice fed a highfat 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 UPR.

Original languageEnglish
Pages (from-to)3404-3415
Number of pages12
JournalDiabetes
Volume63
Issue number10
DOIs
StatePublished - Oct 1 2014

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Palmitates
Protein Biosynthesis
Sirolimus
Islets of Langerhans
Unfolded Protein Response
Polyribosomes
RNA
Nonesterified Fatty Acids
Proteins
Insulin
Hyperplasia
Fatty Acids
Phosphorylation
Diet

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Palmitate induces mRNA translation and increases ER protein load in islet ß-cells via activation of the mammalian target of rapamycin pathway. / Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K.; Templin, Andrew T.; Kulkarni, Rohit N.; Evans-Molina, Carmella; Mirmira, Raghu.

In: Diabetes, Vol. 63, No. 10, 01.10.2014, p. 3404-3415.

Research output: Contribution to journalArticle

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