Mechanisms of STAT3 activation in the liver of FXR knockout mice
Mechanisms of STAT3 activation in the liver of FXR knockout mice
复制标题
FXR 敲除小鼠肝脏中 STAT3 激活的机制。
DOI：
10.1152/ajpgi.00155.2013
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发表时间：
2013-12-01
影响因子：
4.5
通讯作者：
Guo, Grace L.
中科院分区：
文献类型：
--
作者：
Li, Guodong;Zhu, Yan;Guo, Grace L.
法尼醇X受体（Farnesoid X receptor，FXR，Nr 1h 4）是一种配体激活的转录因子，属于核受体超家族。FXR在维持胆汁酸（BA）稳态中至关重要，FXR（-/-）小鼠会发生胆汁淤积、炎症和自发性肝肿瘤。信号转导子和转录激活子3（STAT 3）被认为是调节肝脏生长的重要因子，而STAT 3又被其靶基因细胞因子信号转导抑制子3（SOCS 3）所反馈抑制。在FXR（-/-）小鼠肝脏中检测到STAT 3的强活化。然而，FXR缺乏时STAT 3激活的机制仍然难以捉摸。使用野生型（WT）和FXR（-/-）小鼠检测肝脏中的STAT 3通路活化。体内BA喂养或剥夺用于确定BA在STAT 3激活中的作用，体外分子方法用于确定FXR对SOCS 3的直接转录调控。STAT 3在FXR（-/-）小鼠中被激活，但在WT小鼠中未被激活。BA喂养增加，但剥夺考来烯胺减少，血清炎症标志物和STAT 3激活。此外，Socs 3基因被确定为直接FXR靶基因。升高的BA和炎症，沿着降低的SOCS 3，共同促成FXR（-/-）小鼠肝脏中STAT 3信号传导途径的激活。本研究提示STAT 3的组成性激活可能是FXR（-/-）小鼠肝癌发生的一种机制。
Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice.