The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice
The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice
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DOI：
10.1016/j.ajpath.2016.05.006
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发表时间：
2016-09-01
影响因子：
6
通讯作者：
You, Min
中科院分区：
文献类型：
--
作者：
Cai, Yan;Jogasuria, Alvin;You, Min
我们之前已经证明，乙醇介导的脂钙素-2 （LCN2）升高与小鼠酒精性脂肪性肝病（AFLD）的发展密切相关。在此，我们旨在了解乙醇诱导LCN2的功能意义，并探讨其潜在机制。我们在体外细胞酒精性脂肪变性模型和动物研究中评估了LCN2的作用，动物研究使用野生型和LCN2敲除小鼠，用补充乙醇的Lieber-DeCarli饮食喂养4周。在酒精性脂肪变性的细胞模型中，重组LCN2或LCN2的过表达加剧了乙醇诱导的脂肪积累，而在暴露于乙醇的肝细胞中，敲低LCN2可防止脂肪变性。与此一致的是，去除LCN2部分但显著地减轻了小鼠的酒精性脂肪性肝损伤。从机制上讲，LCN2通过破坏多种信号通路介导乙醇在肝脏中的有害作用，包括异常的烟酰胺磷酸核糖基转移酶-sirtuin 1轴，内分泌代谢调节成纤维细胞生长因子15/19信号通路，以及伴侣介导的自噬受损。最后，与健康人肝脏相比，来自AFLD患者的肝脏样本中几种lcn2调控分子的基因表达较低。我们的研究证明了LCN2在AFLD发展中的关键和因果作用，并表明靶向LCN2可能对人类AFLD的治疗具有重要价值。
We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferase-sirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, Liver samples from patients with AFLD had lower gene expression of several LCN2-regualted molecules. Our study demonstrated a pivotal and causal role of LCN2 in the development of AFLD and suggested that targeting the LCN2 could be of great value for the treatment of human AFLD.