title: Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine II, Gastroenterology and Hepatology, University Hospital, Mannheim, Germany. steven.dooley@med.ma.uni-heidelberg.de
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.forename: Jafar
authors.initials: J
authors.lastname: Hamzavi
authors.forename: Loredana
authors.initials: L
authors.lastname: Ciuclan
authors.forename: Patricio
authors.initials: P
authors.lastname: Godoy
authors.forename: Iryna
authors.initials: I
authors.lastname: Ilkavets
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ehnert
authors.forename: Elke
authors.initials: E
authors.lastname: Ueberham
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
authors.forename: Stephan
authors.initials: S
authors.lastname: Kanzler
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf
authors.forename: Honglei
authors.initials: H
authors.lastname: Weng
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
mesh_terms: D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D002460:Cell Line; D002470:Cell Survival; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D006509:Hepatitis B / Q000150:complications / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012552:Schistosomiasis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen; D002251:Carbon Tetrachloride