Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Am J Physiol Gastrointest Liver Physiol. 2021 Jun 1;320(6):G958-G968. doi: 10.1152/ajpgi.00370.2020. Epub 2021 Mar 31.
Grb2-associated binder 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction by receptor tyrosine kinases that are receptors for various growth factors and plays an important role in rapid liver regeneration after partial hepatectomy and during acute hepatitis. On the other hand, mild liver regeneration is induced in livers of individuals with chronic hepatitis, where hepatocyte apoptosis is persistent; however, the impact of Gab1 on such livers remains unclear. We examined the role of Gab1 in chronic hepatitis. Gab1 knockdown enhanced the decrease in cell viability and apoptosis induced by ABT-737, a Bcl-2/-xL/-w inhibitor, in BNL.CL2 cells, while cell viability and caspase activity were unchanged in the absence of ABT-737. ABT-737 treatment induced Gab1 cleavage to form p35-Gab1. p35-Gab1 was also detected in the livers of mice with hepatocyte-specific Mcl-1 knockout (KO), which causes persistent hepatocyte apoptosis. Gab1 deficiency exacerbated hepatocyte apoptosis in Mcl-1 KO mice with posttranscriptional downregulation of Bcl-XL. In BNL.CL2 cells treated with ABT-737, Gab1 knockdown posttranscriptionally suppressed Bcl-xL expression, and p35-Gab1 overexpression enhanced Bcl-xL expression. Gab1 deficiency in Mcl-1 KO mice activated STAT3 signaling in hepatocytes, increased hepatocyte proliferation, and increased the incidence of liver cancer with the exacerbation of liver fibrosis. In conclusion, Gab1 is cleaved in the presence of apoptotic stimuli and forms p35-Gab1 in hepatocytes. In chronic liver injury, the role of Gab1 in suppressing apoptosis and reducing liver damage, fibrosis, and tumorigenesis is more important than its role in liver regeneration. Grb2-associated binder 1 (Gab1) is known to contribute to liver regeneration after acute liver injury. However, in chronic liver diseases, Gab1 plays a greater role in suppressing hepatocyte apoptosis than in liver regeneration, resulting in suppression of hepatocyte proliferation, liver fibrosis, and liver carcinogenesis.
Grb2 相关结合蛋白 1（Gab1）是一种衔接蛋白，对于受体酪氨酸激酶介导的细胞内信号转导非常重要，这些受体是各种生长因子的受体，并在部分肝切除后的快速肝再生和急性肝炎中发挥重要作用。另一方面，慢性肝炎患者的肝脏会出现轻度再生，其中肝细胞凋亡持续存在；然而，Gab1 对这些肝脏的影响尚不清楚。我们研究了 Gab1 在慢性肝炎中的作用。在 BNL.CL2 细胞中，Gab1 敲低增强了 Bcl-2/-xL/-w 抑制剂 ABT-737 诱导的细胞活力下降和细胞凋亡，而在不存在 ABT-737 的情况下，细胞活力和半胱天冬酶活性没有变化。ABT-737 处理诱导 Gab1 切割形成 p35-Gab1。在具有肝细胞特异性 Mcl-1 敲除（KO）的小鼠肝脏中也检测到 p35-Gab1，这导致持续的肝细胞凋亡。Mcl-1 KO 小鼠中 Gab1 缺失加剧了 Bcl-XL 转录后下调导致的肝细胞凋亡。在用 ABT-737 处理的 BNL.CL2 细胞中，Gab1 敲低转录后抑制了 Bcl-xL 的表达，而过表达 p35-Gab1 增强了 Bcl-xL 的表达。Mcl-1 KO 小鼠中 Gab1 缺失激活了肝细胞中的 STAT3 信号通路，增加了肝细胞增殖，并增加了肝癌的发生率，同时加剧了肝纤维化。总之，在存在凋亡刺激的情况下，Gab1 被切割形成 p35-Gab1 在肝细胞中。在慢性肝损伤中，Gab1 抑制细胞凋亡和减轻肝损伤、纤维化和肿瘤发生的作用比其在肝再生中的作用更为重要。Grb2 相关结合蛋白 1（Gab1）已知在急性肝损伤后有助于肝再生。然而，在慢性肝病中，Gab1 在抑制肝细胞凋亡方面的作用大于肝再生，导致抑制肝细胞增殖、肝纤维化和肝癌发生。
