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首页> 外文期刊>The journal of clinical investigation >Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice
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Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice

机译：p53表达的增加诱导小鼠和人类肝细胞合成CTGF，并导致小鼠肝纤维化

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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 Mdm2, 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.
机译：肿瘤抑制因子p53与非癌症相关疾病的发病机制有关，例如胰岛素抵抗，心力衰竭和早期衰老。另外，在患有纤维化性肝病的个体的肝细胞中已经观察到p53的积累，但是其意义尚不清楚。在本文中，我们将肝细胞中的p53激活与肝纤维化机械性地联系在一起。小鼠中编码Mdm2（一种促进p53降解的蛋白质）基因的肝细胞特异性缺失导致结缔组织生长因子（CTGF;肝纤维化主开关）的肝细胞合成，肝细胞凋亡增加和自发性肝纤维化。同时去除p53完全消除了该表型。与野生型对照相比，在两种肝纤维化模型中，具有肝细胞特异性p53缺失的小鼠表现出相似水平的肝细胞凋亡，但降低了肝纤维化和肝CTGF表达。这些数据的临床意义通过两个观察结果得到了强调。首先，p53通过抑制miR-17-92上调人肝癌细胞系中的CTGF。其次，人肝样品显示CTGF和p53调控的基因表达之间存在相关性，而后者在纤维化肝中均增加。这项研究表明p53诱导CTGF表达并促进肝纤维化，提示p53 / CTGF途径可能是治疗肝纤维化的治疗靶标。

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