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  • Cunha, Daniel A., et al. (author)
  • Thrombospondin 1 protects pancreatic beta-cells from lipotoxicity via the PERK-NRF2 pathway
  • 2016
  • In: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 23:12, s. 1995-2006
  • Journal article (peer-reviewed)abstract
    • The failure of beta-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional beta-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in beta-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 beta-cell death. These findings shed light on the mechanisms leading to beta-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.
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