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

Gastroenterology. 2008 Aug;135(2):642-59. doi: 10.1053/j.gastro.2008.04.038. Epub 2008 May 15.


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 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-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 collagens, and improved CCl(4)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carbon Tetrachloride
  • Cell Line
  • Cell Survival
  • Cell Transdifferentiation*
  • Cells, Cultured
  • Collagen / metabolism
  • Disease Models, Animal
  • Gene Expression Profiling / methods
  • Hepatitis B / complications
  • Hepatitis B / metabolism
  • Hepatitis B / pathology
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Schistosomiasis / complications
  • Schistosomiasis / metabolism
  • Schistosomiasis / pathology
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism*
  • Time Factors
  • Transforming Growth Factor beta / metabolism*


  • SMAD7 protein, human
  • Smad7 Protein
  • Smad7 protein, mouse
  • Transforming Growth Factor beta
  • Collagen
  • Carbon Tetrachloride