RNA-sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate

  1. Décio L Eizirik1
  1. 1Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB) and
  2. 2Division of Endocrinology, Erasmus Hospital, 1070 Brussels, Belgium
  3. 3Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
  4. 4Functional Bioinformatics (FBI), Centre Nacional d'Anàlisi Genòmica (CNAG), 08028 Barcelona, Spain
  5. 5Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) and
  6. 6Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, OX3 7LJ
  7. 7Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
  8. 8Laboratório Nacional de Computação Cientifica (LNCC), 25651-076 Petropolis, Rio de Janeiro, Brazil.
  1. Corresponding author: Miriam Cnop Email: mcnop{at}ulb.ac.be

Abstract

Pancreatic β-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause β-cell failure and contribute to diabetes development in genetically predisposed individuals.

Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling β-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6.

This human islet transcriptome study identified novel mechanisms of palmitate-induced β-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the β-cell level.

  • Received September 10, 2013.
  • Accepted December 14, 2013.

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