CYP2J2 overexpression attenuates nonalcoholic fatty liver disease induced by high-fat diet in mice
CYP2J2 overexpression attenuates nonalcoholic fatty liver disease induced by high-fat diet in mice
复制标题
CYP2J2 过表达可减轻高脂饮食诱导的小鼠非酒精性脂肪肝。
DOI：
10.1152/ajpendo.00366.2014
复制
发表时间：
2015-01-15
影响因子：
5.1
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
--
作者：
Chen, Guangzhi;Xu, Renfan;Wang, Dao Wen
细胞色素P-450环氧合酶衍生的环氧二十碳三烯酸（epoxyeicosatrienoic acids，ESTs）具有多种生物活性，包括有效的血管扩张、抗炎、抗凋亡、抗氧化和心血管保护作用。肝脏具有丰富的环氧合酶表达和高水平的EET产生;然而，环氧合酶在肝脏疾病中的作用仍有待阐明。在这项研究中，我们研究了内皮特异性CYP 2 J2过表达（Tie 2-CYP 2 J2-Tr）小鼠对高脂饮食诱导的非酒精性脂肪性肝病（NAFLD）的保护作用。在高脂饮食24周后，与对照组相比，Tie 2-CYP 2 J2-Tr小鼠显示出减弱的NAFLD。与野生型对照小鼠相比，Tie 2-CYP 2 J2-Tr小鼠显示血浆甘油三酯水平和肝脏脂质蓄积显著降低，肝功能改善，炎症反应减少，肝脏氧化应激增加较少。这些作用与抑制NF-κB/JNK信号通路活化和增强Tie 2-CYP 2 J2-Tr小鼠体内抗氧化防御系统有关。我们还证明了14，15-EET处理保护HepG 2细胞免受棕榈酸诱导的炎症和氧化应激。14，15-EET可抑制软脂酸诱导的HepG 2细胞NF-κB/JNK信号通路、丙二醛生成、谷胱甘肽水平、活性氧产生、NADPH氧化酶和抗氧化酶表达的变化。总之，这些结果突出了EET在脂毒性相关炎症和氧化应激中的新作用，并揭示了EET介导的抗炎和抗氧化作用的新分子机制，这可能有助于设计预防和治疗NAFLD的新疗法。
Cytochrome P-450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti-inflammatory, antiapoptotic, and antioxidatant effects, and cardiovascular protection. Liver has abundant epoxygenase expression and high levels of EET production; however, the roles of epoxygenases in liver diseases remain to be elucidated. In this study, we investigated the protection against high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in mice with endothelial-specific CYP2J2 overexpression (Tie2-CYP2J2-Tr). After 24 wk of high-fat diet, Tie2-CYP2J2-Tr mice displayed attenuated NAFLD compared with controls. Tie2-CYP2J2-Tr mice showed significantly decreased plasma triglyceride levels and liver lipid accumulation, improved liver function, reduced inflammatory responses, and less increase in hepatic oxidative stress than wild-type control mice. These effects were associated with inhibition of NF-κB/JNK signaling pathway activation and enhancement of the antioxidant defense system in Tie2-CYP2J2-Tr mice in vivo. We also demonstrated that 14,15-EET treatment protected HepG2 cells against palmitic acid-induced inflammation and oxidative stress. 14,15-EET attenuated palmitic acid-induced changes in NF-κB/JNK signaling pathways, malondialdehyde generation, glutathione levels, reactive oxygen species production, and NADPH oxidase and antioxidant enzyme expression in HepG2 cells in vitro. Together, these results highlight a new role for CYP epoxygenase-derived EETs in lipotoxicity-related inflammation and oxidative stress and reveal a new molecular mechanism underlying EETs-mediated anti-inflammatory and antioxidant effects that could aid in the design of new therapies for the prevention and treatment of NAFLD.