{"title":"棕榈酸通过激活神经酰胺信号通路诱导β细胞铁变态反应","authors":"Maojun Guo , Xiaolong Huang , Junhan Zhang , Ying Huang , Ying Tang , Honghua Wen , Yanan Xu , Shaokun Zhang , Xiao Wei , Shuoshuo Sun , Qun Zhu","doi":"10.1016/j.yexcr.2024.114134","DOIUrl":null,"url":null,"abstract":"<div><p>Individuals with type 2 diabetes mellitus frequently display heightened levels of palmitic acid (PA) in their serum, which may lead to β-cell damage. The involvement of ferroptosis, a form of oxidative cell death in lipotoxic β-cell injury remains uncertain. Here, we have shown that PA induces intracellular lipid peroxidation, increases intracellular Fe<sup>2+</sup> content and decreases intracellular glutathione peroxidase 4 (GPX4) expression. Furthermore, PA causes distinct changes in pancreatic islets and INS-1 cells, such as mitochondrial atrophy and increased membrane density. Furthermore, the presence of the ferroptosis inhibitor has a significant mitigating effect on PA-induced β-cell damage. Mechanistically, PA increased ceramide content and c-Jun N-terminal kinase (JNK) phosphorylation. The ceramide synthase inhibitor effectively attenuated PA-induced β-cell damage and GPX4/Fe<sup>2+</sup> abnormalities, while inhibiting JNK phosphorylation. Additionally, the JNK inhibitor SP600125 improved PA-induced cell damage. In conclusion, by promoting ceramide synthesis, PA inhibited GPX4 expression and increased intracellular Fe<sup>2+</sup> to induce β-cell ferroptosis. Moreover, JNK may be a downstream mechanism of ceramide-triggered lipotoxic ferroptosis in β-cells.</p></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Palmitic acid induces β-cell ferroptosis by activating ceramide signaling pathway\",\"authors\":\"Maojun Guo , Xiaolong Huang , Junhan Zhang , Ying Huang , Ying Tang , Honghua Wen , Yanan Xu , Shaokun Zhang , Xiao Wei , Shuoshuo Sun , Qun Zhu\",\"doi\":\"10.1016/j.yexcr.2024.114134\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Individuals with type 2 diabetes mellitus frequently display heightened levels of palmitic acid (PA) in their serum, which may lead to β-cell damage. The involvement of ferroptosis, a form of oxidative cell death in lipotoxic β-cell injury remains uncertain. Here, we have shown that PA induces intracellular lipid peroxidation, increases intracellular Fe<sup>2+</sup> content and decreases intracellular glutathione peroxidase 4 (GPX4) expression. Furthermore, PA causes distinct changes in pancreatic islets and INS-1 cells, such as mitochondrial atrophy and increased membrane density. Furthermore, the presence of the ferroptosis inhibitor has a significant mitigating effect on PA-induced β-cell damage. Mechanistically, PA increased ceramide content and c-Jun N-terminal kinase (JNK) phosphorylation. The ceramide synthase inhibitor effectively attenuated PA-induced β-cell damage and GPX4/Fe<sup>2+</sup> abnormalities, while inhibiting JNK phosphorylation. Additionally, the JNK inhibitor SP600125 improved PA-induced cell damage. In conclusion, by promoting ceramide synthesis, PA inhibited GPX4 expression and increased intracellular Fe<sup>2+</sup> to induce β-cell ferroptosis. Moreover, JNK may be a downstream mechanism of ceramide-triggered lipotoxic ferroptosis in β-cells.</p></div>\",\"PeriodicalId\":12227,\"journal\":{\"name\":\"Experimental cell research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-06-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental cell research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014482724002258\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental cell research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014482724002258","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
2 型糖尿病患者血清中的棕榈酸(PA)水平经常升高,这可能会导致β细胞损伤。脂毒性β细胞损伤中的一种氧化性细胞死亡形式--铁变态反应的参与程度仍不确定。在这里,我们发现 PA 会诱导细胞内脂质过氧化,增加细胞内 Fe2+ 含量,降低细胞内谷胱甘肽过氧化物酶 4 (GPX4) 的表达。此外,PA 还会导致胰岛和 INS-1 细胞发生明显变化,如线粒体萎缩和膜密度增加。此外,铁氧化酶抑制剂的存在对 PA 诱导的 β 细胞损伤有显著的缓解作用。从机理上讲,PA 增加了神经酰胺含量和 c-Jun N 端激酶(JNK)磷酸化。神经酰胺合成酶抑制剂在抑制JNK磷酸化的同时,有效减轻了PA诱导的β细胞损伤和GPX4/Fe2+异常。此外,JNK 抑制剂 SP600125 还能改善 PA 诱导的细胞损伤。总之,通过促进神经酰胺的合成,PA 抑制了 GPX4 的表达并增加了细胞内的 Fe2+,从而诱导了β细胞的铁变态反应。此外,JNK可能是神经酰胺诱导β细胞脂毒性铁中毒的下游机制。
Palmitic acid induces β-cell ferroptosis by activating ceramide signaling pathway
Individuals with type 2 diabetes mellitus frequently display heightened levels of palmitic acid (PA) in their serum, which may lead to β-cell damage. The involvement of ferroptosis, a form of oxidative cell death in lipotoxic β-cell injury remains uncertain. Here, we have shown that PA induces intracellular lipid peroxidation, increases intracellular Fe2+ content and decreases intracellular glutathione peroxidase 4 (GPX4) expression. Furthermore, PA causes distinct changes in pancreatic islets and INS-1 cells, such as mitochondrial atrophy and increased membrane density. Furthermore, the presence of the ferroptosis inhibitor has a significant mitigating effect on PA-induced β-cell damage. Mechanistically, PA increased ceramide content and c-Jun N-terminal kinase (JNK) phosphorylation. The ceramide synthase inhibitor effectively attenuated PA-induced β-cell damage and GPX4/Fe2+ abnormalities, while inhibiting JNK phosphorylation. Additionally, the JNK inhibitor SP600125 improved PA-induced cell damage. In conclusion, by promoting ceramide synthesis, PA inhibited GPX4 expression and increased intracellular Fe2+ to induce β-cell ferroptosis. Moreover, JNK may be a downstream mechanism of ceramide-triggered lipotoxic ferroptosis in β-cells.
期刊介绍:
Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.