Increased expression of c-Jun in nonalcoholic fatty liver disease
Increased expression of c-Jun in nonalcoholic fatty liver disease
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DOI：
10.1038/labinvest.2014.3
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发表时间：
2014-04-01
影响因子：
5
通讯作者：
Hellerbrand, Claus
中科院分区：
文献类型：
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作者：
Dorn, Christoph;Engelmann, Julia C.;Hellerbrand, Claus
营养过剩是非酒精性脂肪性肝病（NAFLD）及其晚期形式非酒精性脂肪性肝炎（NASH）的主要原因。我们的目的是开发和表征一种类似于西方社会NASH患者的病理和营养状况的营养模型。用在模拟西方食物的组合物中含有蔗糖、胆固醇和富含饱和脂肪酸的脂肪的NASH诱导饮食（ND）喂养小鼠。12周后，ND喂养的小鼠显示肥胖和葡萄糖耐量受损。在肝脏中，ND喂养导致显著的脂肪变性、肝细胞损伤、炎症和开始纤维化。全转录组基因表达分析和寻找过度表达的转录因子靶位点之间的差异表达的基因确定激活蛋白-1（AP-1）作为最有可能的因素，导致在ND肝脏的转录变化。结合差异表达基因和蛋白质蛋白质相互作用网络分析，确定c-Jun是ND肝脏中最大的连接去调节子网络中的枢纽。因此，ND肝脏显示c-Jun磷酸化和核转位。此外，肝c-Jun表达增强ND喂养小鼠。结合组织芯片技术和免疫组化分析证实了NAFLD患者肝脏c-Jun水平的增强，这与炎症相关，特别是与肝脏脂肪变性的程度相关。总之，我们的新小鼠模型显示了在人NASH中也发现的重要病理变化，并表明c-Jun/AP-1活化是肝脏变化的关键调节因子。NAFLD中c-Jun的缺失可能促进NASH的发展和进展。
Overnutrition is the major cause of nonalcoholic fatty liver disease (NAFLD) and its advanced form nonalcoholic steatohepatitis (NASH). We aimed to develop and characterize a nnurine model, which resembles both the pathology and nutritional situation, of NASH patients in Western societies. Mice were fed with a NASH-inducing diet (ND) containing sucrose, cholesterol and fats rich in saturated fatty acids in a composition, which mimics Western food. After 12 weeks, ND-fed mice revealed obesity and impaired glucose tolerance. In the liver, ND-feeding led to marked steatosis, hepatocellular damage, inflammation and beginning fibrosis. Transcriptome-wide gene expression analysis and search for over-represented transcription factor target sites among the differentially expressed genes identified activator protein-1 (AP-1) as the most likely factor to cause the transcriptional changes in ND livers. Combining differentially expressed gene and protein protein interaction network analysis identified c-Jun as hub in the largest connected deregulated sub-network in ND livers. Accordingly, ND livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun expression was enhanced in ND-fed mice. Combined tissue microarray technology and imnnunohistochemical analysis confirmed enhanced hepatic c-Jun levels in NAFLD patients, which correlated with inflammation, and notably, with the degree of hepatic steatosis. In summary, our new mouse model shows important pathological changes also found in human NASH and indicates c-Jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-Jun in NAFLD likely facilitates development and progression of NASH.