Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells.
Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells.
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作者：
Elsner M;Gehrmann W;Lenzen S
2型糖尿病是一种复杂的疾病，伴有非酯化脂肪酸（NEFA）水平升高，导致β细胞功能障碍和β细胞损失，称为脂毒性。实验证据表明，氧化应激参与脂毒性。在这项研究中，我们分析了活性氧介导的脂毒性的分子机制，在产生胰岛素的RINm 5 F细胞和INS-1 E细胞，以及在原代大鼠胰岛细胞。用MTT法和碘化丙啶（PI）法测定了不同链长的饱和NEFA对胰岛素分泌细胞的毒性。使用过氧化氢酶或超氧化物歧化酶过表达细胞来分析活性氧形成的性质和细胞区室。用新的H2 O2敏感的荧光蛋白HyPer H2 O2形成诱导暴露于棕榈酸进行了测定。只有长链（>C14）饱和NEFA对胰岛素产生细胞有毒。过氧化氢酶在过氧化物酶体和细胞质中的过表达，但不是在线粒体中，显着减少过氧化氢的形成和保护棕榈酸诱导的毒性的细胞。使用Hyper蛋白，在RINm 5 F和INS-1 E胰岛素产生细胞以及原代大鼠胰岛细胞的过氧化物酶体中可直接检测到H2 O2的产生。结果表明，H2 O2的形成在过氧化物酶体，而不是在线粒体负责NEFA诱导的毒性。因此，我们提出了一个新的概念，脂肪酸诱导的β细胞脂毒性介导的活性氧通过过氧化物酶体β-氧化形成。
Type 2 diabetes is a complex disease that is accompanied by elevated levels of nonesterified fatty acids (NEFAs), which contribute to β-cell dysfunction and β-cell loss, referred to as lipotoxicity. Experimental evidence suggests that oxidative stress is involved in lipotoxicity. In this study, we analyzed the molecular mechanisms of reactive oxygen species-mediated lipotoxicity in insulin-producing RINm5F cells and INS-1E cells as well as in primary rat islet cells. The toxicity of saturated NEFAs with different chain lengths upon insulin-producing cells was determined by MTT and propidium iodide (PI) viability assays. Catalase or superoxide dismutase overexpressing cells were used to analyze the nature and the cellular compartment of reactive oxygen species formation. With the new H2O2-sensitive fluorescent protein HyPer H2O2 formation induced by exposure to palmitic acid was determined. Only long-chain (>C14) saturated NEFAs were toxic to insulin-producing cells. Overexpression of catalase in the peroxisomes and in the cytosol, but not in the mitochondria, significantly reduced H2O2 formation and protected the cells against palmitic acid-induced toxicity. With the HyPer protein, H2O2 generation was directly detectable in the peroxisomes of RINm5F and INS-1E insulin-producing cells as well as in primary rat islet cells. The results demonstrate that H2O2 formation in the peroxisomes rather than in the mitochondria are responsible for NEFA-induced toxicity. Therefore, we propose a new concept of fatty acid-induced β-cell lipotoxicity mediated via reactive oxygen species formation through peroxisomal β- oxidation.
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影响因子：
7.1
作者：
GORDON, ES
通讯作者：
GORDON, ES
影响因子：
3.2
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3.7
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