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The hedgehog pathway regulates remodelling responses to biliary obstruction in rats.

Publication ,  Journal Article
Omenetti, A; Popov, Y; Jung, Y; Choi, SS; Witek, RP; Yang, L; Brown, KD; Schuppan, D; Diehl, AM
Published in: Gut
September 2008

BACKGROUND: Chronic biliary obstruction provokes fibrosis and accumulation of immature ductular cells. This fibroductular reaction resolves following biliary decompression, suggesting that it may also be involved in the repair of biliary damage. The hedgehog (Hh) pathway becomes activated in liver after bile duct ligation (BDL), and might modulate hepatic remodelling because Hh ligands are potent morphogens. OBJECTIVE: To study the induction of the Hh pathway during progression and resolution of biliary fibrosis, and to clarify whether Hh signalling regulates accumulation of bile duct progenitor cells. DESIGN AND MAIN OUTCOME MEASURES: Livers from rats with BDL were examined by quantitative real-time polymerase chain reaction analysis and immunohistochemistry to identify factors that might stimulate Hh signalling. BDL rats were subjected to Roux-en-Y hepaticojejunostomy (R-Y) to relieve biliary obstruction in order to determine whether these factors and Hh signalling declined as ductular populations and concomitant fibrosis regressed. Cultures of immature ductular cells were treated with putative Hh inducers and Hh ligands to confirm their functional relevance. RESULTS: BDL increased expression of platelet-derived growth factor-BB (PDGF-BB) and sonic hedgehog (Shh), downregulated hedgehog-interacting protein (Hip), activated Hh signalling, and expanded populations of Hh-responsive ductular cells that expressed pancyotkeratin, a liver progenitor cell marker. After R-Y, Hip remained suppressed, expression of PDGF-BB and Shh gradually declined, and populations of hedgehog-responsive ductular cells regressed. In cultured ductular cells, PDGF-BB treatment induced Shh expression, and incubation with Shh inhibited apoptotic activity. CONCLUSIONS: These results identify a mechanism for activation of the Hh pathway during cholestasis and suggest that Hh signalling regulates ductular cell accumulation after biliary injury.

Duke Scholars

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

September 2008

Volume

57

Issue

9

Start / End Page

1275 / 1282

Location

England

Related Subject Headings

  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats, Sprague-Dawley
  • Rats
  • Proto-Oncogene Proteins c-sis
  • Platelet-Derived Growth Factor
  • Male
  • Ligands
  • Hedgehog Proteins
  • Gene Expression Regulation
 

Citation

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Omenetti, A., Popov, Y., Jung, Y., Choi, S. S., Witek, R. P., Yang, L., … Diehl, A. M. (2008). The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut, 57(9), 1275–1282. https://doi.org/10.1136/gut.2008.148619
Omenetti, A., Y. Popov, Y. Jung, S. S. Choi, R. P. Witek, L. Yang, K. D. Brown, D. Schuppan, and A. M. Diehl. “The hedgehog pathway regulates remodelling responses to biliary obstruction in rats.Gut 57, no. 9 (September 2008): 1275–82. https://doi.org/10.1136/gut.2008.148619.
Omenetti A, Popov Y, Jung Y, Choi SS, Witek RP, Yang L, et al. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut. 2008 Sep;57(9):1275–82.
Omenetti, A., et al. “The hedgehog pathway regulates remodelling responses to biliary obstruction in rats.Gut, vol. 57, no. 9, Sept. 2008, pp. 1275–82. Pubmed, doi:10.1136/gut.2008.148619.
Omenetti A, Popov Y, Jung Y, Choi SS, Witek RP, Yang L, Brown KD, Schuppan D, Diehl AM. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut. 2008 Sep;57(9):1275–1282.

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

September 2008

Volume

57

Issue

9

Start / End Page

1275 / 1282

Location

England

Related Subject Headings

  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats, Sprague-Dawley
  • Rats
  • Proto-Oncogene Proteins c-sis
  • Platelet-Derived Growth Factor
  • Male
  • Ligands
  • Hedgehog Proteins
  • Gene Expression Regulation