Thrombospondin 1 protects pancreatic β-cells from lipotoxicity via the PERK-NRF2 pathway

Cell Death Differ. 2016 Dec;23(12):1995-2006. doi: 10.1038/cdd.2016.89. Epub 2016 Sep 2.

Abstract

The failure of β-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional β-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in β-cell survival during lipotoxic stress in rat, mouse and human models. THBS1 acts from within the endoplasmic reticulum to activate PERK and NRF2 and induce a protective antioxidant defense response against palmitate. Prolonged palmitate exposure causes THBS1 degradation, oxidative stress, activation of JNK and upregulation of PUMA, culminating in β-cell death. These findings shed light on the mechanisms leading to β-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Survival / drug effects
  • Cytoprotection / drug effects*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Female
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipids / toxicity*
  • Male
  • Mice
  • Middle Aged
  • Models, Biological
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Palmitic Acid / toxicity
  • Proteolysis / drug effects
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Thrombospondin 1 / metabolism*
  • eIF-2 Kinase / metabolism*

Substances

  • Antioxidants
  • Apoptosis Regulatory Proteins
  • Lipids
  • NF-E2-Related Factor 2
  • Thrombospondin 1
  • Palmitic Acid
  • PERK kinase
  • eIF-2 Kinase
  • JNK Mitogen-Activated Protein Kinases