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Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling
ABSTRACT: BACKGROUND/AIMS: Profibrogenic TGF-β signaling in hepatic stellate cells is modulated during transdifferentiation. Strategies to abrogate TGF-β effects provide promising antifibrotic results, however, in vivo data regarding Smad activation during fibrogenesis are scarce. Methods: Here, liv...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2006
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933087/ https://www.ncbi.nlm.nih.gov/pubmed/17125595 http://dx.doi.org/10.1111/j.1582-4934.2006.tb00535.x |
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author | Seyhan, H Hamzavi, J Wiercinska, Eliza Gressner, A M Mertens, P R Kopp, J Horch, R E Breitkopf, Katja Dooley, S |
author_facet | Seyhan, H Hamzavi, J Wiercinska, Eliza Gressner, A M Mertens, P R Kopp, J Horch, R E Breitkopf, Katja Dooley, S |
author_sort | Seyhan, H |
collection | PubMed |
description | ABSTRACT: BACKGROUND/AIMS: Profibrogenic TGF-β signaling in hepatic stellate cells is modulated during transdifferentiation. Strategies to abrogate TGF-β effects provide promising antifibrotic results, however, in vivo data regarding Smad activation during fibrogenesis are scarce. Methods: Here, liver fibrosis was assessed subsequent to bile duct ligation by determining liver enzymes in serum and collagen deposition in liver tissue. Activated hepatic stellate cells were identified by immunohistochemistry and immunoblots for alpha smooth muscle actin. Cellular localization of Smad3 and Smad7 proteins was demonstrated by immunohistochemistry. RTPCR for Smad4 and Smad7 was conducted with total RNA and Northern blot analysis for Smad7 with mRNA. Whole liver lysates were prepared to detect Smad2/3/4 and phospho- Smad2/3 by Western blotting. Results: Cholestasis induces TGF-β signaling via Smad3 in vivo, whereas Smad2 phosphorylation was only marginally increased. Smad4 expression levels were unchanged. Smad7 expression was continuously increasing with duration of cholestasis. Hepatocytes of fibrotic lesions exhibited nuclear staining Smad3. In contrast to this, Smad7 expression was localized to activated hepatic stellate cells. Conclusions: Hepatocytes of damaged liver tissue display increased TGF-β signaling via Smad3. Further, negative feedback regulation of TGF-β signaling by increased Smad7 expression in activated hepatic stellate cells occurs, however does not interfere with fibrogenesis. |
format | Online Article Text |
id | pubmed-3933087 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-39330872015-07-06 Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling Seyhan, H Hamzavi, J Wiercinska, Eliza Gressner, A M Mertens, P R Kopp, J Horch, R E Breitkopf, Katja Dooley, S J Cell Mol Med Original Article ABSTRACT: BACKGROUND/AIMS: Profibrogenic TGF-β signaling in hepatic stellate cells is modulated during transdifferentiation. Strategies to abrogate TGF-β effects provide promising antifibrotic results, however, in vivo data regarding Smad activation during fibrogenesis are scarce. Methods: Here, liver fibrosis was assessed subsequent to bile duct ligation by determining liver enzymes in serum and collagen deposition in liver tissue. Activated hepatic stellate cells were identified by immunohistochemistry and immunoblots for alpha smooth muscle actin. Cellular localization of Smad3 and Smad7 proteins was demonstrated by immunohistochemistry. RTPCR for Smad4 and Smad7 was conducted with total RNA and Northern blot analysis for Smad7 with mRNA. Whole liver lysates were prepared to detect Smad2/3/4 and phospho- Smad2/3 by Western blotting. Results: Cholestasis induces TGF-β signaling via Smad3 in vivo, whereas Smad2 phosphorylation was only marginally increased. Smad4 expression levels were unchanged. Smad7 expression was continuously increasing with duration of cholestasis. Hepatocytes of fibrotic lesions exhibited nuclear staining Smad3. In contrast to this, Smad7 expression was localized to activated hepatic stellate cells. Conclusions: Hepatocytes of damaged liver tissue display increased TGF-β signaling via Smad3. Further, negative feedback regulation of TGF-β signaling by increased Smad7 expression in activated hepatic stellate cells occurs, however does not interfere with fibrogenesis. John Wiley & Sons, Ltd 2006-10 2008-10-09 /pmc/articles/PMC3933087/ /pubmed/17125595 http://dx.doi.org/10.1111/j.1582-4934.2006.tb00535.x Text en |
spellingShingle | Original Article Seyhan, H Hamzavi, J Wiercinska, Eliza Gressner, A M Mertens, P R Kopp, J Horch, R E Breitkopf, Katja Dooley, S Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling |
title | Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling |
title_full | Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling |
title_fullStr | Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling |
title_full_unstemmed | Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling |
title_short | Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling |
title_sort | liver fibrogenesis due to cholestasis is associated with increased smad7 expression and smad3 signaling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933087/ https://www.ncbi.nlm.nih.gov/pubmed/17125595 http://dx.doi.org/10.1111/j.1582-4934.2006.tb00535.x |
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