Inhibition of 5-lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model.
Inhibition of 5-lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model.
复制标题
5-脂氧合酶抑制剂齐留通在高脂饮食诱导的非酒精性脂肪肝疾病进展模型中的抑制作用
DOI：
10.22038/ijbms.2017.9482
复制
发表时间：
2017-11
影响因子：
2.2
通讯作者：
Zhao Q
中科院分区：
文献类型：
--
作者：
Ma K;Chen Y;Liang X;Miao J;Zhao Q
目的：花生四烯酸/5-脂氧合酶（AA/5-LOX）通路连接脂质代谢和促炎细胞因子，两者都与非酒精性脂肪性肝病（NAFLD）的发生发展有关。因此，本研究旨在探讨AA/5-LOX通路在NAFLD进展中的作用，以及5-LOX抑制剂zileuton在该模型中的作用。材料与方法：通过饲喂高饱和脂肪饲料（HFD）建立NAFLD进展动物模型。采用肝功能、HE染色、NAFLD活性评分（NAS）评价NAFLD进展情况。我们检测了脂质代谢底物：游离脂肪酸（FFA）和AA，产物：半胱氨酸-白三烯（CysLTs），以及AA/5-LOX通路关键酶PLA2和5-LOX基因和蛋白水平的变化。此外，我们确定给药zileuton（1-[1-（1-苯并噻吩-2-基）乙基]-1-羟基脲）是否会延迟或逆转NAFLD的进展途径。结果：通过肝转氨酶活性、苏木精-伊红（HE）染色和NAS分析，建立了大鼠NAFLD进展模型。AA/5-LOX通路的底物和产物浓度随着NAFLD的进展而增加。PLA2和5-LOX的mRNA和蛋白表达均增强。此外，zileuton抑制了AA/5-LOX途径，逆转了转氨胺活性和NAS的增加。结论：AA/5-LOX通路促进NAFLD的进展，可通过zileuton逆转。
Objective(s): Arachidonic Acid/5-lipoxygenase (AA/5-LOX) pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD). Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model. Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD). Liver function, HE staining, NAFLD activity score (NAS) were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA) and AA, products: cysteinyl-leukotrienes (CysLTs), and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA2 and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea) was administrated. Results: Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE) staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA2 and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS. Conclusion: AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.