Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Mol Cell Biol. 2011 Jun;31(12):2392-403. doi: 10.1128/MCB.01218-10. Epub 2011 Apr 11.
Chronic exposure of the liver to hepatotoxic agents initiates an aberrant wound healing response marked by proinflammatory, as well as fibrotic, changes, leading to compromised organ structure and function. In a variety of pathological states, correlative links have been established between tissue fibrosis and the expression of transcription factors associated with the induction of epithelial-mesenchymal cell transition (EMT) programs similar to those engaged during development. However, the role played by endogenously derived, EMT-associated transcription factors in fibrotic states in vivo remains undefined. Using a mouse model of acute liver fibrosis, we demonstrate that hepatocytes upregulate the expression of the zinc finger transcriptional repressor, Snail1, during tissue remodeling. Hepatocyte-specific ablation of Snail1 demonstrates that this transcription factor plays a key role in liver fibrosis progression in vivo by triggering the proximal genetic programs that control multiple aspects of fibrogenesis, ranging from growth factor expression and extracellular matrix biosynthesis to the ensuing chronic inflammatory responses that characterize this class of pathological disorders.
肝脏慢性暴露于肝毒性物质会引发异常的伤口愈合反应，表现为炎症和纤维化改变，导致器官结构和功能受损。在多种病理状态下，组织纤维化与与诱导上皮-间充质细胞转化 (EMT) 程序相关的转录因子的表达之间存在相关性，这些 EMT 程序类似于在发育过程中涉及的程序。然而，内源性 EMT 相关转录因子在体内纤维化状态中所起的作用尚不清楚。我们使用急性肝纤维化的小鼠模型证明，在组织重塑过程中，肝细胞上调锌指转录抑制因子 Snail1 的表达。肝细胞特异性敲除 Snail1 表明，该转录因子通过触发控制纤维化发生的多个方面的近端遗传程序，在体内肝纤维化进展中发挥关键作用，这些方面包括生长因子表达和细胞外基质生物合成，以及随后的慢性炎症反应，这些都是这类病理紊乱的特征。
