6533b82bfe1ef96bd128e0f3

RESEARCH PRODUCT

Hepatocyte-Specific Smad7 Expression Attenuates TGF-β–Mediated Fibrogenesis and Protects Against Liver Damage

subject

description

Background & Aims The profibrogenic role of transforming growth factor (TGF)-β 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-β 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 CCl 4 -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-β 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-β signaling and EMT, resulted in less accumulation of interstitial collagens, and improved CCl 4 -provoked liver damage and fibrosis scores compared with controls. Conclusions The data indicate that hepatocytes undergo TGF-β–dependent EMT-like phenotypic changes and actively participate in fibrogenesis. Furthermore, ablation of TGF-β signaling specifically in this cell type is sufficient to blunt the fibrogenic response.