Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes.
Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes.
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DOI：
10.1002/hep.23102
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发表时间：
2009-09
期刊：
影响因子：
13.5
通讯作者：
Brigstock, David R.
中科院分区：
文献类型：
--
作者：
Tong, ZhenYue;Chen, Ruju;Alt, Daniel S.;Kemper, Sherri;Perbal, Bernard;Brigstock, David R.
结缔组织生长因子（CCN 2）是一种基质细胞蛋白，在许多纤维化疾病中上调，并与转化生长因子β共表达。CCN 2促进活化的肝星状细胞中的纤维形成和存活，并且损伤或纤维化的肝脏含有上调水平的CCN 2，其由多种不同的细胞类型（包括肝细胞）产生。为了研究CCN 2在体内的作用，创建转基因FVB小鼠，其中将人CCN 2基因置于白蛋白增强子启动子的控制下以提高肝细胞CCN 2水平。hCCN 2 mRNA的产生和CCN 2蛋白水平的升高在转基因肝脏中得到证实，而内源性小鼠CCN 2的水平在转基因小鼠和野生型小鼠之间相当。转基因动物的肝脏组织学和肝功能检查未受影响。然而，在长期给予四氯化碳（CCl 4）后，表达α-平滑肌肌动蛋白（α-SMA）的细胞和胶原沉积增加，这是hCCN 2转基因剂量的函数（即hccn 2 +/+ > hccn 2 +/- > hccn 2-/-）。此外，CCl 4诱导的血清透明质酸、α-SMA或酸溶性胶原的肝组织水平以及α-SMA、胶原α1（I）、基质金属蛋白酶-2或金属蛋白酶组织抑制剂-1的mRNA表达在转基因小鼠中高于野生型小鼠。转基因小鼠胆管结扎后两周也表现出增强的肝胶原沉积。结论：在体内转基因小鼠肝细胞中产生升高的CCN 2水平不会导致肝损伤或纤维化本身，但使肝脏更容易受到其他纤维化刺激的伤害性作用。这些研究支持CCN 2在肝纤维化中的核心作用，并证明了微环境在调节CCN 2的促纤维化作用中的作用。
Connective tissue growth factor (CCN2) is a matricellular protein that is up-regulated in many fibrotic disorders and co-expressed with transforming growth factor beta. CCN2 promotes fibrogenesis and survival in activated hepatic stellate cells, and injured or fibrotic liver contains up-regulated levels of CCN2 which are produced by a variety of different cell types, including hepatocytes. To investigate CCN2 action in vivo, transgenic FVB mice were created in which the human CCN2 gene was placed under the control of the albumin enhancer promoter to elevate hepatocyte CCN2 levels. Production of hCCN2 mRNA and elevated CCN2 protein levels was demonstrated in transgenic livers, while levels of endogenous mouse CCN2 were comparable between transgenic and wild-type mice. Liver histology and liver function tests were unaffected in transgenic animals. However, after chronic administration of carbon tetrachloride (CCl4), alpha-smooth muscle actin (α-SMA)-expressing cells and collagen deposition were increased as a function of the dosage of the hCCN2 transgene (i.e. hccn2+/+ > hccn2+/- > hccn2-/-). Moreover, CCl4-induced serum hyaluronic acid, hepatic tissue levels of α-SMA or acid-soluble collagen, and mRNA expression of α-SMA, collagen α1 (I), matrix metalloprotease-2, or tissue inhibitor of metalloprotease-1 were greater in transgenic mice than in wild-type mice. Transgenic mice also exhibited enhanced hepatic deposition of collagen two weeks after bile duct ligation Conclusion: Production of elevated CCN2 levels in hepatocytes of transgenic mice in vivo does not cause hepatic injury or fibrosis per se but renders the livers more susceptible to the injurious actions of other fibrotic stimuli. These studies support for a central role of CCN2 in hepatic fibrosis and demonstrate a role of the micro-environment in regulating the pro-fibrotic action of CCN2.
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影响因子：
4.1
作者：
Leask, Andrew;Chen, Shaoqiong;Brigstock, David R.
通讯作者：
Brigstock, David R.
影响因子：
9.3
作者：
Gressner, Axel M.;Yagmur, Eray;Stanzel, Sven
通讯作者：
Stanzel, Sven
影响因子：
29.4
作者：
Hillebrandt, S;Goos, C;Lammert, F
通讯作者：
Lammert, F
影响因子：
3.5
作者：
Hoshijima, M;Hattori, T;Takigawa, M
通讯作者：
Takigawa, M
DOI：
10.1016/j.biocel.2008.07.025
发表时间：
2009-04
影响因子：
4
作者：
Chen, Chih-Chiun;Lau, Lester F.
通讯作者：
Lau, Lester F.