Liver fibrosis is a progressive pathologic process that involves deposition of 
excess extracellular matrix leading to distorted architecture and culminating in 
cirrhosis. The role of transforming growth factor-beta (TGF-beta) as a key 
molecule in the development and progression of hepatic fibrosis via the 
activation of hepatic stellate cells, among other fibroblast populations, is 
without controversy. We hereby show that TGF-beta1 induces an 
epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro. 
EMT state was marked by significant upregulation of alpha(1)(I) collagen mRNA 
expression and type I collagen deposition. Similar changes were found in a 
"normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes 
are capable of EMT changes and type I collagen synthesis. We also show that in 
hepatocytes in the EMT state, TGF-beta1 induces the snail-1 transcription factor 
and activates the Smad2/3 pathway. Evidence for a central role of the 
TGF-beta1/Smad pathway is further supported by the inhibition of EMT by Smad4 
silencing using small interference RNA technology. In conclusion, TGF-beta1, a 
known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating 
phenotypic changes and plasticity in the form of EMT, resulting in collagen 
deposition. Our findings support a potentially crucial role for EMT in the 
development and progression of hepatic fibrogenesis.