Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

Abstract

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.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01218-10.

ACKNOWLEDGMENTS

S.J.W. is supported by NIH grant CA116516 and E.G.N. by NIH grant DK-46282. Work performed in this study was also supported by MDRTC Cell and Molecular Biology Core NIH grant P60 DK020572.

We thank B. Omary (University of Michigan) for helpful discussion. We acknowledge A. Willis for assistance with the analysis of microarray data, as well as B. Moore and T. Moore (University of Michigan) for assistance with flow cytometry analyses.

E.G.N. has licensed the anti-FSP1 antibody to Millipore.