Novel role for amphiregulin in protection from liver injury
Novel role for amphiregulin in protection from liver injury
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DOI：
10.1074/jbc.m413344200
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发表时间：
2005-05-13
影响因子：
4.8
通讯作者：
Avila, MA
中科院分区：
文献类型：
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作者：
Berasain, C;García-Trevijano, ER;Avila, MA
临床上，Fas和Fas配体系统在肝细胞凋亡的发展中起着中心作用，肝细胞凋亡是导致广泛的肝脏疾病的过程。因此，开发旨在抑制肝细胞凋亡的疗法是一个主要问题。表皮生长因子受体的激活已被证明可以将存活信号传递给肝细胞。为了了解Fas介导的肝损伤过程中表皮生长因子受体配体的内源性反应，我们研究了Fas激动剂抗体激发的小鼠肝脏中表皮生长因子、转化生长因子α、肝素结合表皮生长因子样生长因子、β细胞素、表皮调节蛋白和双调蛋白的表达。双调蛋白的表达，几乎检测不到健康的肝脏，显着上调。双调蛋白的管理废除Fas介导的小鼠肝损伤，并在原代肝细胞中表现出直接的抗凋亡作用。双调蛋白激活Akt和信号转导子和转录激活子-3存活通路，并上调Bcl-xL表达。双调蛋白敲除小鼠在没有任何有害治疗的情况下显示出慢性肝损伤的迹象，并且响应于致死剂量的Fas激动剂抗体而比野生型小鼠死得更快。相反，这些小鼠对亚致死性肝损伤更具抵抗力，支持慢性肝损伤可以预处理肝细胞诱导对随后细胞死亡的抵抗的假设。这些结果表明，双调蛋白是一种保护性因子诱导响应肝损伤，它可能是治疗肝脏疾病。
Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.