Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma
Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma
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DOI：
10.1073/pnas.0409722102
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发表时间：
2005-03-01
影响因子：
11.1
通讯作者：
Fausto, N
中科院分区：
文献类型：
--
作者：
Campbell, JS;Hughes, SD;Fausto, N
血小板衍生生长因子（PDGF）配体家族成员已知在伤口愈合和纤维化疾病中起重要作用。我们发现，PDGF - C的瞬时和稳定表达都会导致肝纤维化的发展，其特征是胶原蛋白以细胞周围和血管周围的模式沉积，类似于人类酒精性和非酒精性脂肪性肝病。通过染色和羟脯氨酸含量所证实的PDGF - C转基因小鼠的纤维化，之前会出现肝星状细胞的活化和增殖，这可通过胶原蛋白、α - 平滑肌肌动蛋白和胶质纤维酸性蛋白染色显示出来，并且在8到12个月大时会出现肝腺瘤和肝细胞癌。许多已知的促纤维化基因，包括β1型转化生长因子、PDGF受体α和β以及基质金属蛋白酶 - 1和 - 2的组织抑制剂，在4周龄时肝脏表达增加。PDGF受体α和β蛋白水平的升高与细胞外调节激酶 - 1和 - 2以及蛋白激酶B的活化有关。在9个月大时，PDGF - C转基因小鼠肝脏增大，伴有纤维化增加、脂肪变性、细胞异型增生和肝细胞癌。这些研究表明，PDGF - C在肝脏中的表达诱导了许多促纤维化途径，这表明该生长因子可能作为纤维化的起始因子。此外，PDGF - C转基因小鼠代表了一种研究肝纤维化进展为肿瘤发生的独特模型。
Members of the platelet-derived growth factor (PDGF) ligand family are known to play important roles in wound healing and fibrotic disease. We show that both transient and stable expression of PDGF-C results in the development of liver fibrosis consisting of the deposition of collagen in a pericellular and perivenular pattern that resembles human alcoholic and nonalcoholic fatty liver disease. Fibrosis in PDGF-C transgenic mice, as demonstrated by staining and hydroxyproline content, is preceded by activation and proliferation of hepatic stellate cells, as shown by collagen, a-smooth muscle actin and glial fibrillary acidic protein staining and between 8 and 12 months of age is followed by the development of liver adenomas and hepatocellular carcinomas. The hepatic expression of a number of known profibrotic genes, including type beta1 TGF, PDGF receptors alpha and beta, and tissue inhibitors of matrix metalloproteinases-1 and -2, increased by 4 weeks of age. Increased PDGF receptor alpha and beta protein levels were associated with activation of extracellular regulated kinase-1 and -2 and protein kinase B. At 9 months of age, PDGF-C transgenic mice had enlarged livers associated with increased fibrosis, steatosis, cell dysplasia, and hepatocellular carcinomas. These studies indicate that hepatic expression of PDGF-C induces a number of profibrotic pathways, suggesting that this growth factor may act as an initiator of fibrosis. Moreover, PDGF-C transgenic mice represent a unique model for the study of hepatic fibrosis progressing to tumorigenesis.