Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice
Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice
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DOI：
10.1152/ajpgi.00289.2014
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发表时间：
2015-04-01
影响因子：
4.5
通讯作者：
Takehara, Tetsuo
中科院分区：
文献类型：
--
作者：
Kizu, Takashi;Yoshida, Yuichi;Takehara, Tetsuo
Grb2相关结合蛋白1(GAB1)接头蛋白可放大一系列生长因子/受体酪氨酸激酶下游的信号。尽管这些信号与肝纤维化有关，但GAB1的作用仍不清楚。为了阐明GAB1的作用，我们观察了肝细胞特异性GAB1条件基因敲除(Gab1CKO)小鼠在胆管结扎(BDL)时的肝纤维化程度。与对照组相比，Gab1CKO小鼠BDL后肝纤维化加重，肝成纤维细胞活化。肝细胞GAB1的抗纤维化作用被另一种公认的慢性注射四氯化碳的小鼠肝纤维化模型进一步证实。BDL后，Gab1CKO小鼠也表现出肝损伤加重，肝细胞增殖减少，肝脏炎症加重。此外，利用基因芯片分析了GAB1介导的信号在肝纤维化中的潜在分子机制，并鉴定了肝纤维化促进因子趋化因子(C-C基序)配体5(CCL5)在BDL后在Gab1CKO小鼠肝脏中上调。有趣的是，使用从对照组和Gab1CKO小鼠分离的原代肝细胞进行的体外研究表明，GAB1的丢失导致内毒素刺激下肝细胞CCL5合成增加。最后，CCL5的药理拮抗作用可减轻BDL诱导的Gab1CKO小鼠肝纤维化。总之，我们的结果表明，肝细胞GAB1是肝纤维化所必需的，而肝细胞CCL5可能是这一过程的重要贡献者。因此，我们提出了一种新的肝细胞GAB1在肝纤维化中的抗纤维化作用。
Grb2-associated binder 1 (Gab1) adaptor protein amplifies signals downstream of a broad range of growth factors/receptor tyrosine kinases. Although these signals are implicated in liver fibrogenesis, the role of Gab1 remains unclear. To elucidate the role of Gab1, liver fibrosis was examined in hepatocyte-specific Gab1-conditional knockout (Gab1CKO) mice upon bile duct ligation (BDL). Gab1CKO mice developed exacerbated liver fibrosis with activation of hepatic myofibroblasts after BDL compared with control mice. The antifibrotic role of hepatocyte Gab1 was further confirmed by another well-established mouse model of liver fibrosis using chronic injections of carbon tetrachloride. After BDL, Gab1CKO mice also displayed exacerbated liver injury, decreased hepatocyte proliferation, and enhanced liver inflammation. Furthermore, cDNA microarray analysis was used to investigate the potential molecular mechanisms of the Gab1-mediated signal in liver fibrosis, and the fibrosis-promoting factor chemokine (C-C motif) ligand 5 (Ccl5) was identified as upregulated in the livers of Gab1CKO mice following BDL. Interestingly, in vitro studies using primary hepatocytes isolated from control and Gab1CKO mice revealed that the loss of Gab1 resulted in increased hepatocyte CCL5 synthesis upon lipopolysaccharide stimulation. Finally, pharmacological antagonism of CCL5 reduced BDL-induced liver fibrosis in Gab1CKO mice. In conclusion, our results demonstrate that hepatocyte Gab1 is required for liver fibrosis and that hepatocyte CCL5 could be an important contributor to this process. Thus, we present a novel antifibrotic function of hepatocyte Gab1 in liver fibrogenesis.