Fibrogenesis in Pediatric Cholestatic Liver Disease: Role of Taurocholate and Hepatocyte-Derived Monocyte Chemotaxis Protein-1 in Hepatic Stellate Cell Recruitment

Ramm, GA, Shepherd, RW, Hoskins, AC, Greco, SA, Ney, AD, Pereira, TN, Bridle, Kim R., Doecke, JD, Meikle, PJ, Turlin, B and Lewindon, PJ (2009) Fibrogenesis in Pediatric Cholestatic Liver Disease: Role of Taurocholate and Hepatocyte-Derived Monocyte Chemotaxis Protein-1 in Hepatic Stellate Cell Recruitment. Hepatology, 49 2: 533-544. doi:10.1002/hep.22637


Author Ramm, GA
Shepherd, RW
Hoskins, AC
Greco, SA
Ney, AD
Pereira, TN
Bridle, Kim R.
Doecke, JD
Meikle, PJ
Turlin, B
Lewindon, PJ
Title Fibrogenesis in Pediatric Cholestatic Liver Disease: Role of Taurocholate and Hepatocyte-Derived Monocyte Chemotaxis Protein-1 in Hepatic Stellate Cell Recruitment
Journal name Hepatology   Check publisher's open access policy
ISSN 0270-9139
Publication date 2009-02-01
Year available 2009
Sub-type Article (original research)
DOI 10.1002/hep.22637
Open Access Status Not Open Access
Volume 49
Issue 2
Start page 533
End page 544
Total pages 12
Editor Blei, Andres & Bologna, Gregory
Place of publication USA
Publisher John Wiley & Sons, Inc.
Language eng
Subject 920501 Child Health
110307 Gastroenterology and Hepatology
C1
Abstract Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis, however its cause(s) and early pathogenesis are unclear. We hypothesised that a bile acid-induced Ductular Reaction (DR) drives fibrogenesis. We evaluated the DR by cytokeratin-7 immunohistochemistry in liver biopsies, staged for fibrosis, from 60 children with CFLD and demonstrated that the DR was significantly correlated with hepatic fibrosis stage and biliary taurocholate levels. To examine the mechanisms involved in DR induction liver progenitor cells (LPCs) were treated with taurocholate and key events in DR evolution were assessed: LPC proliferation, LPC biliary differentiation and hepatic stellate cell (HSC) chemotaxis. Taurocholate induced a time-dependent increase in LPC proliferation and expression of genes associated with cholangiocyte differentiation (cytokeratin-19, connexin-43, integrin-β4 and γ-glutamyltranspeptidase [GGT]), while the hepatocyte specification marker HNF4α was suppressed. Functional cholangiocyte differentiation was demonstrated via increased acetylated α-tubulin and SOX9 proteins, the number of primary cilia(+) LPCs and increased active GGT enzyme secretion. Taurocholate induced LPCs to release MCP-1, MIP1α and RANTES into conditioned medium causing HSC chemotaxis, which was inhibited by anti-MIP1α. Immunofluorescence confirmed chemokine expression localized to CK7(+) DR and LPCs in CFLD liver biopsies. This study suggests that taurocholate is involved in initiating functional LPC biliary differentiation and the development of the DR, with subsequent induction of chemokines that drive HSC recruitment in CFLD.
Keyword CYSTIC-FIBROSIS
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 290220
913-003
5U01DK62452
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Thu, 03 Sep 2009, 18:51:28 EST by Mr Andrew Martlew on behalf of Medicine - Princess Alexandra Hospital