Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Hepatology. 2010 Apr;51(4):1319-26. doi: 10.1002/hep.23469.
Growth hormone (GH) resistance and low serum levels of insulinlike growth factor 1 (IGF-1) are common features in human liver fibrosis and cirrhosis. Signal transducer and activator of transcription 5 (STAT5) controls several vital functions in the liver, including GH-mediated transcription of IGF-1. To investigate the role of STAT5 in liver fibrogenesis, we specifically deleted the Stat5a/b locus both in hepatocytes and cholangiocytes in the multidrug resistance gene 2 knockout (Mdr2(-/-)) mouse model of cholestasis. Double knockout mice develop an early and severe liver fibrosis phenotype, accompanied by perturbed expression of key regulators of bile acid homeostasis. Deletion of Stat5 resulted in GH resistance, and IGF-1 levels in serum were undetectable. We could observe reduced expression of important hepatoprotective genes, such as epidermal growth factor receptor (Egfr), hepatocyte nuclear factor 6 (Hnf6), prolactin receptor (Prlr), and leukemia inhibitory factor receptor (Lifr) as well as increased numbers of apoptotic hepatocytes.
Our data suggest that loss of STAT5 sensitizes hepatocytes to bile acid-induced damage and apoptosis caused by disruption of GH-induced transcription of Igf-1 and down-regulation of hepatoprotective genes. These findings could contribute to the understanding of liver fibrosis and future treatment strategies for liver fibrosis.
生长激素（GH）抵抗和胰岛素样生长因子 1（IGF-1）血清水平低是人类肝纤维化和肝硬化的常见特征。信号转导子和转录激活子 5（STAT5）控制肝脏的几个重要功能，包括 GH 介导的 IGF-1 转录。为了研究 STAT5 在肝纤维化发生中的作用，我们在多药耐药基因 2 敲除（Mdr2（-/-））鼠模型的肝纤维化中特异性地在肝细胞和胆管细胞中缺失 Stat5a/b 基因座。双重敲除小鼠表现出早期和严重的肝纤维化表型，伴随着胆汁酸稳态关键调节剂的表达失调。Stat5 的缺失导致 GH 抵抗，血清中的 IGF-1 水平无法检测到。我们可以观察到重要的肝保护基因的表达减少，如表皮生长因子受体（Egfr）、肝细胞核因子 6（Hnf6）、催乳素受体（Prlr）和白血病抑制因子受体（Lifr），以及凋亡肝细胞数量增加。
我们的数据表明，STAT5 的缺失使肝细胞对胆汁酸诱导的损伤和 GH 诱导的 Igf-1 转录中断以及肝保护基因下调引起的细胞凋亡敏感。这些发现有助于理解肝纤维化和未来的肝纤维化治疗策略。
