Protective effects of lipocalin-2 (LCN2) in acute liver injury suggest a novel function in liver homeostasis
Protective effects of lipocalin-2 (LCN2) in acute liver injury suggest a novel function in liver homeostasis
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DOI：
10.1016/j.bbadis.2013.01.014
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发表时间：
2013-05-01
影响因子：
6.2
通讯作者：
Weiskirchen, Ralf
中科院分区：
文献类型：
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作者：
Borkham-Kamphorst, Erawan;de Leur, Eddy van;Weiskirchen, Ralf
Lipocalin-2在中毒、感染、炎症和其他形式的细胞应激等有害条件下表达。实验性肝损伤诱导受损肝细胞快速、持续地产生Lcn2。然而，Lcn2在肝脏中的确切生物学功能仍不清楚。在本研究中，Lcn2-1小鼠被暴露于短期给予CCl_4、脂多糖和刀豆蛋白A，或接受胆管结扎。随后的损伤通过肝功能分析、QRT-PCR检测趋化因子和细胞因子的表达、肝组织Western印迹、组织学和TUNEL检测来评估。对肝病患者血清Lcn2水平进行检测和评价。急性CCl_4中毒可加重Lcn2/小鼠肝损伤，表现为肝组织转氨酶水平升高，炎性细胞因子和趋化因子如IL-1β、IL-6、肿瘤坏死因子等表达增加。和MCP-1/CCL2，导致STAT1、STAT3和JNIK通路持续激活。Lcn2/小鼠肝细胞出现脂滴聚集，细胞凋亡率增加。刀豆蛋白A和脂多糖模型均可见肝细胞凋亡。在慢性模型(4周胆管结扎或8周CCl4应用)中，与对照组相比，Lcn2-1小鼠的纤维化程度略有增加。有趣的是，与对照组相比，肝病患者的血清Lcn2水平显著升高，但在肝硬变和非肝硬变患者之间没有观察到差异。Lcn2(-/-)表达上调是反映肝损伤的可靠指标，对急性肝损伤有明显的保护作用。LCN2(-/-)水平与肝纤维化程度无关，但与炎症程度呈显着正相关。(C)2013爱思唯尔B.V.保留所有权利。
Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury induces rapid and sustained LCN2 production by injured hepatocytes. However, the precise biological function of LCN2 in liver is still unknown. In this study, LCN2-1 mice were exposed to short term application of CCl4, lipopolysaccharide and Concanavalin A, or subjected to bile duct ligation. Subsequent injuries were assessed by liver function analysis, qRT-PCR for chemokine and cytokine expression, liver tissue Western blot, histology and TUNEL assay. Serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Acute CCl4 intoxication showed increased liver damage in LCN2 / mice indicated by higher levels of aminotransferases, and increased expression of inflammatory cytokines and chemokines such as IL-1 beta, IL-6, TNF-ty. and MCP-1/CCl2, resulting in sustained activation of STAT1, STAT3 and JNIK pathways. Hepatocytes of LCN2 / mice showed lipid droplet accumulation and increased apoptosis. Hepatocyte apoptosis was confirmed in the Concanavalin A and lipopolysaccharide models. In chronic models (4 weeks bile duct ligation or 8 weeks CCl4 application), LCN2-1 mice showed slightly increased fibrosis compared to controls. Interestingly, serum LCN2 levels in diseased human livers were significantly higher compared to controls, but no differences were observed between cirrhotic and non-cirrhotic patients. Upregulation of LCN2(-/-) is a reliable indicator of liver damage and has significant hepato-protective effect in acute liver injury. LCN2(-/-) levels provide no correlation to the degree of liver fibrosis but show significant positive correlation to inflammation instead. (C) 2013 Elsevier B.V. All rights reserved.