Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice
Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice
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DOI：
10.1016/s0168-8278(03)00460-4
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发表时间：
2003-12-01
影响因子：
25.7
通讯作者：
Gores, GJ
中科院分区：
文献类型：
--
作者：
Feldstein, AE;Canbay, A;Gores, GJ
背景/目的：肝脏脂肪变性通过不清楚的机制使肝脏对损伤和炎症敏感。由于Fas与肝脏损伤和炎症有关，因此在肝脏脂肪变性模型中检测了Fas的表达和对Fas信号的敏感性。方法：小鼠饲喂碳水化合物饲料，对照组给予标准饲料。用Jo2抗体检测细胞对Fas的增敏作用。在体外实验中，HepG2细胞与或不与长链脂肪酸(油酸：棕榈酸2：1)的混合物孵育。结果：高热量饲料喂养的小鼠出现肝脏脂肪变性、高脂血症、胰岛素抵抗和高瘦素血症，这些都是人类综合征的特征。与瘦肉型动物相比，Fas在肝细胞中的表达增加，并与细胞毒信号转导有关。事实上，在给予Fas激动剂JO-2后，肥胖动物的肝细胞凋亡、肝脏损伤和趋化因子的产生都有所加剧。在游离脂肪酸存在的情况下培养的Hep G2细胞也出现了细胞脂肪变性，上调了Fas的表达，并对Fas激动剂诱导的细胞凋亡更加敏感。结论：总的来说，这些数据暗示Fas是肥胖相关性脂肪肝与肝损伤易感性增加之间的联系。(C)2003年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background/Aims: Hepatic steatosis sensitizes the liver to injury and inflammation by unclear mechanisms. Because Fas has been linked to liver injury and inflammation, Fas expression and sensitization to Fas signaling was examined in models of hepatic steatosis.Methods: Mice were fed a carbohydrate diet while control animals received standard chow. Sensitization to Fas was examined following administration of Jo2 antibody. For the in vitro experiments, HepG2 cells were incubated with or without a mixture of long chain fatty acids (2:1 oleate:palmitate). Sensitization of the cells to Fas was examined using the CH11 antibody.Results: Mice fed a high caloric diet developed hepatic steatosis, hyperlipidemia, insulin resistance, and hyperleptinemia, all features of the human syndrome. Fas expression in hepatocytes was increased as compared to lean animals and was coupled to cytotoxic signaling. Indeed, hepatocyte apoptosis, liver injury and chemokine generation were all accentuated in obese animals following administration of Jo-2, a Fas agonist. Hep G2 cells cultured in the presence of free fatty acids also developed 'cellular steatosis', upregulated Fas expression and were more sensitive to apoptosis by a Fas agonist.Conclusions: Collectively, these data implicate Fas as a link between obesity associated fatty liver and increased susceptibility to liver damage. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.