Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage

Background & Aims: The profibrogenic role of transforming growth factor (TGF)-beta in liver has mostly been attributed to hepatic stellate cell activation and excess, matrix synthesis. Hepatocytes are believed to contribute to increased rates of apoptosis. Methods: Primary hepatocyte outgrowths and AML12 cells were used as an in vitro model to detect TGF-beta effects on the cellular phenotype and expression profile. Furthermore, a transgenic mouse model was used to determine the outcome of hepatocyte-specific Smad7 expression on fibrogenesis following CCl4-dependent damage. Samples from patients with chronic liver diseases were assessed for (partial) epithelial-to-mesenchymal transition (EMT) in hepatocytes. Results: In primary cell cultures and in vivo, the majority of hepatocytes survive despite activated TGF-beta signaling. These cells display phenotypic changes and express proteins characteristic for (partial) EMT and fibrogenesis. Experimental expression of Smad7 in hepatocytes of mice attenuated TGF-beta signaling and EMT, resulted in less accumulation of interstitial colla ens, and improved CCl4-provoked liver damage and fibrosis scores compared with controls. Conclusions: The data indicate that hepatocytes undergo TGF-beta-dependent EMT-like phenotypic changes and actively participate in fibrogenesis. Furthermore, ablation of TGF-beta signaling specifically in this cell type is sufficient to blunt the fibrogenic response.