Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice
Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice
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DOI：
10.1172/jci44957
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
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作者：
Kodama, Takahiro;Takehara, Tetsuo;Hayashi, Norio
肿瘤抑制因子 p53 与胰岛素抵抗、心力衰竭和早衰等非癌症相关疾病的发病机制有关。此外，在患有纤维化肝病的个体的肝细胞中观察到p53的积累，但其意义尚不清楚。在此，我们在机制上将肝细胞中的 p53 激活与肝纤维化联系起来。小鼠肝细胞特异性删除编码Mchm2（一种促进p53降解的蛋白质）的基因，导致肝细胞合成结缔组织生长因子（CTGF；肝纤维化总开关），增加肝细胞凋亡和自发性肝纤维化；同时去除p53完全消除了这种表型。与野生型对照相比，肝细胞特异性p53缺失的小鼠在两种肝纤维化模型中表现出相似的肝细胞凋亡水平，但肝纤维化和肝CTGF表达降低。两项观察结果强调了这些数据的临床意义。首先，p53 通过抑制 miR-17-92 上调人肝细胞癌细胞系中的 CTGF。其次，人类肝脏样本显示 CTGF 和 p53 调节基因表达之间存在相关性，这两种基因表达在纤维化肝脏中均有所增加。本研究揭示p53诱导CTGF表达并促进肝纤维化，提示p53/CTGF通路可能成为治疗肝纤维化的治疗靶点。
The tumor suppressor p53 has been implicated in the pathogenesis of non-cancer-related conditions such as insulin resistance, cardiac failure, and early aging. In addition, accumulation of p53 has been observed in the hepatocytes of individuals with fibrotic liver diseases, but the significance of this is not known. Herein, we have mechanistically linked p53 activation in hepatocytes to liver fibrosis. Hepatocyte-specific deletion in mice of the gene encoding Mchm2, a protein that promotes p53 degradation, led to hepatocyte synthesis of connective tissue growth factor (CTGF; the hepatic fibrogenic master switch), increased hepatocyte apoptosis, and spontaneous liver fibrosis; concurrent removal of p53 completely abolished this phenotype. Compared with wild-type controls, mice with hepatocyte-specific p53 deletion exhibited similar levels of hepatocyte apoptosis but decreased liver fibrosis and hepatic CTGF expression in two models of liver fibrosis. The clinical significance of these data was highlighted by two observations. First, p53 upregulated CTGF in a human hepatocellular carcinoma cell line by repressing miR-17-92. Second, human liver samples showed a correlation between CTGF and p53-regulated gene expression, which were both increased in fibrotic livers. This study reveals that p53 induces CTGF expression and promotes liver fibrosis, suggesting that the p53/CTGF pathway may be a therapeutic target in the treatment of liver fibrosis.