Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea.
Institute of Medical Science, Yeungnam University College of Medicine, Daegu, Republic of Korea.
Free Radic Biol Med. 2019 Apr;134:505-515. doi: 10.1016/j.freeradbiomed.2019.02.004. Epub 2019 Feb 5.
Altered metabolism is implicated in the pathogenesis of beta-cell failure in type 2 diabetes (T2D). Plasma and tissue levels of ceramide species play positive roles in inflammatory and oxidative stress responses in T2D. However, oxidative targets and mechanisms underlying ceramide signaling are unclear. We investigated the role of CD36-dependent redoxosome (redox-active endosome), a membrane-based signaling agent, in ceramide-induced beta-cell dysfunction and failure. Exposure of beta cells to C2-ceramide (N-acetyl-sphingosine) induced a CD36-dependent non-receptor tyrosine kinase Src-mediated redoxosome (Vav2-Rac1-NOX) formation. Activated Rac1-GTP-NADPH oxidase complex induced c-Jun-N-terminal kinase (JNK) activation and nuclear factor (NF)-kB transcription, which was associated with thioredoxin-interacting protein (TXNIP) upregulation and thioredoxin activity suppression. Upregulated JNK expression induced p66Shc serine36 phosphorylation and peroxiredoxin-3 hyperoxidation, causing beta-cell apoptosis via mitochondrial dysfunction. CD36 inhibition by sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA blocked C2-ceramide-induced redoxosome activation, thereby decreasing JNK-dependent p66Shc serine36 phosphorylation. CD36 inhibition downregulated TXNIP expression and promoted thioredoxin activity via enhanced thioredoxin reductase activity, which prevented peroxiredoxin-3 oxidation. CD36 inhibition potentiated glucose-stimulated insulin secretion and prevented beta-cell apoptosis. Our results reveal a new role of CD36 during early molecular events that lead to Src-mediated redoxosome activation, which contributes to ceramide-induced pancreatic beta-cell dysfunction and failure.
代谢改变与 2 型糖尿病（T2D）中β细胞衰竭的发病机制有关。在 T2D 中，神经酰胺种类的血浆和组织水平在炎症和氧化应激反应中起积极作用。然而，神经酰胺信号的氧化靶标和机制尚不清楚。我们研究了 CD36 依赖性氧化还原体（氧化活性内体），一种基于膜的信号转导剂，在神经酰胺诱导的β细胞功能障碍和衰竭中的作用。β细胞暴露于 C2-神经酰胺（N-乙酰神经氨酸）会诱导 CD36 依赖性非受体酪氨酸激酶Src 介导的氧化还原体（Vav2-Rac1-NOX）形成。激活的 Rac1-GTP-NADPH 氧化酶复合物诱导 c-Jun-N 末端激酶（JNK）激活和核因子（NF）-kB 转录，这与硫氧还蛋白相互作用蛋白（TXNIP）上调和硫氧还蛋白活性抑制有关。上调的 JNK 表达诱导 p66Shc 丝氨酸 36 磷酸化和过氧化物还原酶-3 过氧化，通过线粒体功能障碍导致β细胞凋亡。通过磺基-N-琥珀酰亚胺辛酯（SSO）或 CD36 siRNA 抑制 CD36 阻断 C2-神经酰胺诱导的氧化还原体激活，从而减少 JNK 依赖性 p66Shc 丝氨酸 36 磷酸化。CD36 抑制通过增强硫氧还蛋白还原酶活性下调 TXNIP 表达并促进硫氧还蛋白活性，从而防止过氧化物还原酶-3 氧化。CD36 抑制增强了葡萄糖刺激的胰岛素分泌并防止了β细胞凋亡。我们的研究结果揭示了 CD36 在导致 Src 介导的氧化还原体激活的早期分子事件中的新作用，这有助于神经酰胺诱导的胰腺β细胞功能障碍和衰竭。
