Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage.
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.
Dooley
Steven
S
Department of Medicine II, Gastroenterology and Hepatology, University Hospital, Mannheim, Germany. steven.dooley@med.ma.uni-heidelberg.de
Hamzavi
Jafar
J
Ciuclan
Loredana
L
Godoy
Patricio
P
Ilkavets
Iryna
I
Ehnert
Sabrina
S
Ueberham
Elke
E
Gebhardt
Rolf
R
Kanzler
Stephan
S
Geier
Andreas
A
Breitkopf
Katja
K
Weng
Honglei
H
Mertens
Peter R
PR
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*
C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen; D002251:Carbon Tetrachloride