LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease.
LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease.
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DOI：
10.18632/oncotarget.5163
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发表时间：
2015-12-08
期刊：
影响因子：
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通讯作者：
Alisi A
中科院分区：
文献类型：
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作者：
Ceccarelli S;Panera N;Mina M;Gnani D;De Stefanis C;Crudele A;Rychlicki C;Petrini S;Bruscalupi G;Agostinelli L;Stronati L;Cucchiara S;Musso G;Furlanello C;Svegliati-Baroni G;Nobili V;Alisi A
脂多糖（LPS）目前被认为是非酒精性脂肪性肝病（NAFLD）发病机制和进展的主要参与者之一。在这里，我们的目的是研究 LPS 诱导的 TNF-α 因子 (LITAF) 在诱导非酒精性脂肪性肝炎 (NASH) 的促炎和促纤维化表型中的可能作用。我们发现患有 NAFLD 的儿童在不同的肝脏驻留细胞中表现出 LITAF 表达增加，这与肝脏炎症和纤维化的组织学特征相关。小鼠和人肝星状细胞 (HSC) 中 LITAF 总表达和核表达增加。此外，LPS 在克隆性肌成纤维细胞 HSC LX-2 细胞系中诱导 LITAF 依赖性 IL-1β、IL-6 和 TNF-α 转录，而这种作用受到 LITAF 沉默的阻碍。我们首次在 HSC 中证明，LITAF 对这些细胞因子启动子的募集是 LPS 依赖性的。然而，通过 p38MAPK 抑制剂防止 LITAF 核转位，在 p65NF-ĸB 的帮助下，IL-6 和 TNF-α 的表达显着降低，而 IL-1β 转录完全需要 LITAF 表达/活性。最后，血浆中的 IL-1β 水平与肝脏中的水平一致，并与 NASH 儿童的 LPS 水平和 LITAF 阳性 HSC 相关。总之，儿童 NAFLD 中更严重的组织学特征与 HSC 中 LITAF 过度表达有关，而 LITAF 反过来又与肝脏和循环 IL-1β 水平相关，概述了 NASH 相关肝损伤的一组潜在生物标志物。体外研究强调了 LITAF 作为 HSC 中 LPS 诱导的促炎症模式的关键调节剂的作用，并建议 p38MAPK 抑制剂作为 NASH 中肝脏炎症的可能治疗方法。
Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH). We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH. In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH.