Thrombospondin 1 protects pancreatic β-cells from lipotoxicity via the PERK-NRF2 pathway
Thrombospondin 1 protects pancreatic β-cells from lipotoxicity via the PERK-NRF2 pathway
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DOI：
10.1038/cdd.2016.89
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发表时间：
2016-12-01
影响因子：
12.4
通讯作者：
Cnop, Miriam
中科院分区：
文献类型：
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作者：
Cunha, Daniel A.;Cito, Monia;Cnop, Miriam
β 细胞的衰竭在 2 型糖尿病的发病机制中起着核心作用，确定改善功能性 β 细胞质量的新方法对于预防/逆转该疾病至关重要。在这里，我们展示了血小板反应蛋白 1 (THBS1) 在大鼠、小鼠和人类模型的脂毒性应激期间对 β 细胞存活的关键新作用。 THBS1 在内质网内发挥作用，激活 PERK 和 NRF2，并诱导针对棕榈酸酯的保护性抗氧化防御反应。长期接触棕榈酸酯会导致 THBS1 降解、氧化应激、JNK 激活和 PUMA 上调，最终导致 β 细胞死亡。这些发现揭示了代谢应激期间导致 β 细胞衰竭的机制，并指出 THBS1 是预防 2 型糖尿病氧化应激的一个有趣的治疗靶点。
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.