Karaca Gamze, Xie Guanhua, Moylan Cynthia, Swiderska-Syn Marzena, Guy Cynthia D, Krüger Leandi, Machado Mariana Verdelho, Choi Steve S, Michelotti Gregory A, Burkly Linda C, Diehl Anna Mae
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina;
Department of Pathology, Duke University Medical Center, Durham, North Carolina;
Am J Physiol Gastrointest Liver Physiol. 2015 Feb 15;308(4):G325-34. doi: 10.1152/ajpgi.00429.2013. Epub 2014 Dec 18.
TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14(+) progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl₄ for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl₄ treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.
肿瘤坏死因子样凋亡弱诱导剂（TWEAK）是双能肝祖细胞的生长因子，这些肝祖细胞表达其受体成纤维细胞生长因子诱导14（Fn14），后者是肿瘤坏死因子受体超家族成员。Fn14⁺祖细胞的积累发生在严重急性酒精性脂肪性肝炎（ASH）中，且与急性死亡率相关。在严重ASH患者中，抑制肿瘤坏死因子-α会增加急性死亡率。本研究的目的是确定敲除Fn14是否能改善饮酒小鼠肝损伤的结局。将野生型（WT）和Fn14基因敲除（KO）小鼠喂食对照高脂Lieber deCarli饮食或含2%乙醇（ETOH）的高脂Lieber deCarli饮食，并腹腔注射四氯化碳2周以诱导肝损伤。在四氯化碳处理后3天或10天对小鼠实施安乐死。评估生存率。通过定量逆转录聚合酶链反应、免疫印迹、羟脯氨酸含量和定量免疫组织化学分析肝组织中的细胞死亡、炎症、增殖、祖细胞积累和纤维化情况。在肝损伤期间，喂食任何一种饮食的WT小鼠中Fn14表达、凋亡、炎症、肝细胞复制、祖细胞和成肌纤维细胞积累以及纤维化均增加。喂食任何一种饮食的小鼠表达相似的TWEAK/Fn14水平，但喂食ETOH的小鼠肿瘤坏死因子-α表达更高。喂食ETOH的组发生更多的凋亡、炎症、纤维化和再生反应。敲除Fn14并未降低肝脏肿瘤坏死因子-α表达，但改善了喂食对照饮食小鼠的所有损伤参数。在喂食ETOH的小鼠中，尽管肝损伤有所改善，但敲除Fn14抑制了肿瘤坏死因子-α诱导并增加了急性死亡率。Fn14介导了在酒精暴露期间急性肝损伤存活所必需的伤口愈合反应。
