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

ABSTRACT: The failure of ?-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional ?-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in ?-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 ?-cell death. These findings shed light on the mechanisms leading to ?-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.

SUBMITTER: Cunha DA 

PROVIDER: S-EPMC5136495 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature