Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae
Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae
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肝脏脂肪酸结合蛋白缺乏会引起斑马鱼幼虫中吡嗪酰胺诱导的氧化应激、炎症和细胞凋亡介导的肝毒性
DOI：
10.1128/aac.01693-16
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发表时间：
2016-10
影响因子：
4.9
通讯作者：
Jiang, Zhenzhou
中科院分区：
文献类型：
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作者：
Chen, Weiyun;Hsiao, Chung-Der;Zhang, Luyong;Jiang, Zhenzhou
吡嗪酰胺（Pyrazinamide， PZA）是一种重要的抗结核药物，但其潜在的肝毒性尚不清楚。本研究探讨了PZA暴露对斑马鱼（Danio rerio）幼虫的影响及其肝毒性机制。将肝脏中表达增强绿色荧光蛋白（EGFP）的转基因斑马鱼幼体与受精后72 h （hpf）的1、2.5和5 mM PZA孵育。选择不同的终点，如死亡率、肝脏大小和形状的形态学变化、组织学变化、转氨酶分析和凋亡、氧化和遗传损伤标志物以及某些基因的表达来评估pza诱导的肝毒性。我们的结果证实了PZA剂量依赖性肝毒性的方式。PZA在斑马鱼幼虫中引起明显的损伤，如肝萎缩、转氨酶水平升高、氧化应激和肝细胞凋亡。为了进一步了解PZA诱导肝毒性的机制，我们检测了暴露于PZA 72 h后斑马鱼幼鱼基因表达水平的变化。本研究结果表明，PZA通过上调肿瘤坏死因子α (TNF-α)、转化生长因子β (TGF-β)等炎性细胞因子，降低肝脏脂肪酸结合蛋白（L-FABP）及其靶基因过氧化物酶体增殖物活化受体α (PPAR-α)的表达水平，引发更严重的氧化应激和肝炎。这些结果表明，L-FABP介导的PPAR-α下调可能是斑马鱼幼鱼肝细胞凋亡引起的肝毒性反应，L-FABP可以作为早期检测pza诱导的斑马鱼幼鱼肝损伤的生物标志物。
ABSTRACT Pyrazinamide (PZA) is an essential antitubercular drug, but little is still known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish (Danio rerio) larvae and the mechanisms underlying its hepatotoxicity. A transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver was incubated with 1, 2.5, and 5 mM PZA from 72 h postfertilization (hpf). Different endpoints such as mortality, morphology changes in the size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as the expression of certain genes were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury in zebrafish larvae, such as liver atrophy, elevations of transaminase levels, oxidative stress, and hepatocyte apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, changes in gene expression levels in zebrafish larvae exposed to PZA for 72 h postexposure (hpe) were determined. The results of this study demonstrated that PZA decreased the expression levels of liver fatty acid binding protein (L-FABP) and its target gene, peroxisome proliferator-activated receptor α (PPAR-α), and provoked more severe oxidative stress and hepatitis via the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β). These findings suggest that L-FABP-mediated PPAR-α downregulation appears to be a hepatotoxic response resulting from zebrafish larva liver cell apoptosis, and L-FABP can be used as a biomarker for the early detection of PZA-induced liver damage in zebrafish larvae.
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DOI：
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发表时间：
1989
期刊：
--
影响因子：
--
作者：
Slivka IuI;Klimniuk Ev;T. Oe
通讯作者：
Slivka IuI;Klimniuk Ev;T. Oe
DOI：
10.3390/ijerph121215012
发表时间：
2015-12-09
影响因子：
--
作者：
Cui Y;Liu W;Xie W;Yu W;Wang C;Chen H
通讯作者：
Chen H
影响因子：
3.5
作者：
Her, GM;Chiang, CC;Wu, JL
通讯作者：
Wu, JL
影响因子：
8.8
作者：
M. Qi;Yao Dang;Qinglong Xu;Liqin Yu;Chunsheng Liu;Yongchao Yuan;Jianghuai Wang
通讯作者：
M. Qi;Yao Dang;Qinglong Xu;Liqin Yu;Chunsheng Liu;Yongchao Yuan;Jianghuai Wang
影响因子：
4.5
作者：
Cheng Zeng;Hong Sun;P. Xie;Jianghuai Wang;Gui-xian Zhang;Nan Chen;Wei Yan;Guangyu Li
通讯作者：
Cheng Zeng;Hong Sun;P. Xie;Jianghuai Wang;Gui-xian Zhang;Nan Chen;Wei Yan;Guangyu Li