title: Thrombospondin 1 protects pancreatic β-cells from lipotoxicity via the PERK-NRF2 pathway.
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.
authors: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors: Daniel A
authors: DA
authors: Cunha
authors: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors: Monia
authors: M
authors: Cito
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors: Per-Ola
authors: PO
authors: Carlsson
authors: Light Microscopy Facility, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors: Jean-Marie
authors: JM
authors: Vanderwinden
authors: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Jeffery D
authors: JD
authors: Molkentin
authors: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors: Marco
authors: M
authors: Bugliani
authors: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors: Piero
authors: P
authors: Marchetti
authors: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors: Décio L
authors: DL
authors: Eizirik
authors: ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.|Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.
authors: Miriam
authors: M
authors: Cnop
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008055:Lipids / Q000633:toxicity*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019308:Palmitic Acid / Q000633:toxicity; D059748:Proteolysis / Q000187:drug effects; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D019700:Thrombospondin 1 / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008055:Lipids; D051267:NF-E2-Related Factor 2; D019308:Palmitic Acid; D019700:Thrombospondin 1; D019892:eIF-2 Kinase