Song Yuxiang, Li Xinwei, Li Yu, Li Na, Shi Xiaoxia, Ding Hongyan, Zhang Yuhang, Li Xiaobing, Liu Guowen, Wang Zhe
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
Apoptosis. 2014 Jun;19(6):984-97. doi: 10.1007/s10495-014-0982-3.
A high plasma concentration of non-esterified fatty acids (NEFAs) is an important pathogenic factor that leads to ketosis and fatty liver in dairy cows. NEFAs may be associated with oxidative stress in dairy cows with ketosis or fatty liver and the subsequent induction of hepatocyte damage. However, the molecular mechanism of NEFAs-induced oxidative stress and whether NEFAs cause apoptosis of hepatocytes are unclear. Therefore, the aim of this study was to investigate the molecular mechanism of NEFAs-induced oxidative liver damage in bovine hepatocytes. The results showed that NEFAs increased oxidative stress, resulting in p38 phosphorylation. High activated p38 increased the expression, nuclear localization and transcriptional activity of p53 and decreased the nuclear localization and transcriptional activity of Nrf2 in bovine hepatocytes treated with high concentrations of NEFAs. High concentrations of NEFAs also promoted the apoptosis of bovine hepatocytes. Both N-acetyl-L-cysteine (NAC) and glucose (GLU) could attenuate the NEFA-induced apoptotic damage. These results indicate that NEFAs activate the ROS-p38-p53/Nrf2 signaling pathway to induce apoptotic damage in bovine hepatocytes.
血浆中非酯化脂肪酸（NEFAs）浓度过高是导致奶牛酮病和脂肪肝的重要致病因素。NEFAs可能与患酮病或脂肪肝的奶牛的氧化应激以及随后的肝细胞损伤诱导有关。然而，NEFAs诱导氧化应激的分子机制以及NEFAs是否会导致肝细胞凋亡尚不清楚。因此，本研究的目的是探讨NEFAs诱导牛肝细胞氧化肝损伤的分子机制。结果表明，NEFAs增加了氧化应激，导致p38磷酸化。高活性的p38增加了高浓度NEFAs处理的牛肝细胞中p53的表达、核定位和转录活性，并降低了Nrf2的核定位和转录活性。高浓度的NEFAs还促进了牛肝细胞的凋亡。N-乙酰-L-半胱氨酸（NAC）和葡萄糖（GLU）均可减轻NEFA诱导的凋亡损伤。这些结果表明，NEFAs激活ROS-p38-p53/Nrf2信号通路，诱导牛肝细胞凋亡损伤。
