RGD Reference Report - The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. - Rat Genome Database

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

Authors: Omenetti, A  Popov, Y  Jung, Y  Choi, SS  Witek, RP  Yang, L  Brown, KD  Schuppan, D  Diehl, AM 
Citation: Omenetti A, etal., Gut. 2008 Sep;57(9):1275-82. doi: 10.1136/gut.2008.148619. Epub 2008 Mar 28.
RGD ID: 11552599
Pubmed: PMID:18375471   (View Abstract at PubMed)
DOI: DOI:10.1136/gut.2008.148619   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
primary biliary cholangitis  ISOHhip (Rattus norvegicus)11552599; 11552599mRNA:decreased expression:RGD 
primary biliary cholangitis  IEP 11552599mRNA:decreased expression:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hhip  (Hedgehog-interacting protein)

Genes (Mus musculus)
Hhip  (Hedgehog-interacting protein)

Genes (Homo sapiens)
HHIP  (hedgehog interacting protein)


Additional Information