Alteration of endoplasmic reticulum lipid rafts contributes to lipotoxicity in pancreatic β-cells

Ebru Boslem, Jacquelyn M. Weir, Gemma MacIntosh, Nancy Sue, James Cantley, Peter J. Meikle, Trevor J. Biden

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

Background: Saturated fatty acids disrupt protein trafficking and promote endoplasmic reticulum (ER) stress in pancreatic β-cells.

Results: Chronic palmitate selectively reduces ER sphingomyelin and cholesterol and disrupts ER lipid rafts.

Conclusion: Altered ER lipid rafts contribute to defective ER protein export.

Significance: This provides novel insights into the mechanisms of β-cell death that underlie type 2 diabetes.

Chronic saturated fatty acid exposure causes β-cell apoptosis and, thus, contributes to type 2 diabetes. Although endoplasmic reticulum (ER) stress and reduced ER-to-Golgi protein trafficking have been implicated, the exact mechanisms whereby saturated fatty acids trigger β-cell death remain elusive. Using mass spectroscopic lipidomics and subcellular fractionation, we demonstrate that palmitate pretreatment of MIN6 β-cells promoted ER remodeling of both phospholipids and sphingolipids, but only the latter was causally linked to lipotoxic ER stress. Thus, overexpression of glucosylceramide synthase, previously shown to protect against defective protein trafficking and ER stress, partially reversed lipotoxic reductions in ER sphingomyelin (SM) content and aggregation of ER lipid rafts, as visualized using Erlin1-GFP. Using both lipidomics and a sterol response element reporter assay, we confirmed that free cholesterol in the ER was also reciprocally modulated by chronic palmitate and glucosylceramide synthase overexpression. This is consistent with the known coregulation and association of SM and free cholesterol in lipid rafts. Inhibition of SM hydrolysis partially protected against ATF4/C/EBP homology protein induction because of palmitate. Our results suggest that loss of SM in the ER is a key event for initiating β-cell lipotoxicity, which leads to disruption of ER lipid rafts, perturbation of protein trafficking, and initiation of ER stress.

Original languageEnglish
Pages (from-to)26569-26582
Number of pages14
JournalJournal of Biological Chemistry
Volume288
Issue number37
DOIs
Publication statusPublished - 13 Sep 2013

Keywords

  • Ceramide
  • Endoplasmic Reticulum Stress
  • Lipotoxicity
  • Pancreatic Islets
  • Trafficking
  • ER Lipid Raft
  • Lipidomics
  • Palmitate
  • Sphingomyelin
  • Type 2 Diabetes

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