FABP7 Protects Astrocytes Against ROS Toxicity via Lipid Droplet Formation
FABP7 Protects Astrocytes Against ROS Toxicity via Lipid Droplet Formation
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DOI：
10.1007/s12035-019-1489-2
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发表时间：
2019-08-01
影响因子：
5.1
通讯作者：
Owada, Yuji
中科院分区：
文献类型：
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作者：
Islam, Ariful;Kagawa, Yoshiteru;Owada, Yuji
脂肪酸结合蛋白（FABPs）结合并内化长链脂肪酸，控制脂质动力学。最近的研究提出FABPs，特别是FABP7参与胶质瘤中脂滴（LD）的形成，但对LD的生理意义知之甚少。在这项研究中，我们试图研究FABP7在小鼠原代星形胶质细胞中的作用，重点关注其对活性氧（ROS）应激的保护作用。在FABP7敲除（KO）星形胶质细胞中，与野生型星形胶质细胞中的ROS诱导相比，ROS诱导显著降低LD积累，提高ROS毒性，并损害硫氧还蛋白（TRX）信号，但不损害过氧化物还蛋白1 （PRX1）信号。因此，在ROS胁迫下，FABP7 KO星形细胞中凋亡信号分子，包括p38丝裂原活化蛋白激酶（MAPK）和应激活化蛋白激酶/c-Jun n-末端激酶（SAPK/JNK）被激活，cleaved caspase 3的表达增加。应用n -乙酰半胱氨酸（NAC）成功地挽救了FABP7 KO星形细胞的ROS毒性。此外，在U87人胶质瘤细胞系中，FABP7过表达比模拟转染显示出更高的LD积累和更高的抗氧化防御酶（TRX， TRX还原酶1 [TRXRD1]）表达，并保护细胞凋亡信号（p38 MAPK， SAPK/JNK和cleaved caspase 3）激活。综上所述，这些数据表明FABP7通过LD形成保护星形胶质细胞免受ROS毒性，为FABP7、脂质稳态和神经精神/神经退行性疾病（包括阿尔茨海默病和精神分裂症）之间的联系提供了新的见解。
Fatty acid-binding proteins (FABPs) bind and internalize long-chain fatty acids, controlling lipid dynamics. Recent studies have proposed the involvement of FABPs, particularly FABP7, in lipid droplet (LD) formation in glioma, but the physiological significance of LDs is poorly understood. In this study, we sought to examine the role of FABP7 in primary mouse astrocytes, focusing on its protective effect against reactive oxygen species (ROS) stress. In FABP7 knockout (KO) astrocytes, ROS induction significantly decreased LD accumulation, elevated ROS toxicity, and impaired thioredoxin (TRX) but not peroxiredoxin 1 (PRX1) signalling compared to ROS induction in wild-type astrocytes. Consequently, activation of apoptosis signalling molecules, including p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and increased expression of cleaved caspase 3 were observed in FABP7 KO astrocytes under ROS stress. N-acetyl L-cysteine (NAC) application successfully rescued the ROS toxicity in FABP7 KO astrocytes. Furthermore, FABP7 overexpression in U87 human glioma cell line revealed higher LD accumulation and higher antioxidant defence enzyme (TRX, TRX reductase 1 [TRXRD1]) expression than mock transfection and protected against apoptosis signalling (p38 MAPK, SAPK/JNK and cleaved caspase 3) activation. Taken together, these data suggest that FABP7 protects astrocytes from ROS toxicity through LD formation, providing new insights linking FABP7, lipid homeostasis, and neuropsychiatric/neurodegenerative disorders, including Alzheimer's disease and schizophrenia.