Abstract
Our previous studies have shown that autophagy mediates the link between ductular reaction (DR) and liver cirrhosis. Whether the subsequent fibrogenic response is regulated by increased autophagy in DR remains unclear. Here, using both human liver specimens and a rat model of liver cirrhosis induced by 2-acetylaminofluorene (AAF) and carbon tetrachloride (CCL4), we explored the involvement of autophagy in regulating mesenchymal transition of ductular cells. Ductular cells from AAF/CCL4 livers exhibited increased autophagy compared to those of normal livers. These cells showed morphological and functional characteristics of mesenchymal cells. Blocking autophagy using bafilomycin A1 or siRNA targeting ATG7 reduced the expression of mesenchymal markers in these ductular cells from AAF/CCL4 livers, indicating a role for autophagy in regulating the mesenchymal phenotype of ductular cells. Furthermore, we show that the mesenchymal transition in DR requires the activation of transforming growth factor-β (TGF-β) signaling in an autophagy-dependent manner. Importantly, in cirrhotic human livers, ductular cells that are positive for LC3B also showed increased expression of TGF-β and fibroblast-specific protein-1. Our data suggest activation of autophagy in ductular cells, and also demonstrate that it is required for the mesenchymal transition during the DR, processes that are critically involved in the pathogenesis of cirrhosis.
Highlights
Ductular reaction (DR) is a common response to injury observed in a variety of liver diseases[1]
We demonstrate increased autophagy in the ductular cells isolated from AAF/CCL4 livers, and that autophagy is required for mesenchymal transition in ductular cells of AAF/CCL4 livers and in cirrhotic human livers
It is believed that autophagy in different types of liver cells may lead to opposite effects on the pathogenesis of fibrosis[11,12,13,14,22]
Summary
Ductular reaction (DR) is a common response to injury observed in a variety of liver diseases[1]. Recent work has presented evidence that starvation-induced autophagy can induce the expression of EMT markers and the invasion of hepatic carcinoma cells in a TGF-β/Smad[3] signaling-dependent manner[16]. These results prompted us to study whether autophagy activation precedes and leads to EMT of ductular cells in liver cirrhosis. We used a model of cirrhosis in the rat, produced by 2-acetylaminofluorene (AAF) and carbon tetrachloride (CCL4) In this model, administration of AAF before and during CCL4 treatment blocks the proliferative hepatocyte response to CCL4-induced necrosis and leads to the emergence of an alternative regenerative pathway characterized by the periportal accumulation of ductular cells, similar to what is commonly reported in human cirrhosis[17]. We demonstrate increased autophagy in the ductular cells isolated from AAF/CCL4 livers, and that autophagy is required for mesenchymal transition in ductular cells of AAF/CCL4 livers and in cirrhotic human livers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
