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 yet assessed
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 Cholestatic liver diseases, such as cystic fibrosis (CF) liver disease and biliary atresia, predominate as causes of childhood cirrhosis. Despite diverse etiologies, the stereotypic final pathway involves fibrogenesis where hepatic stellate cells (HSCs) are recruited, producing excess collagen which initiates biliary fibrosis. A possible molecular determinant of this recruitment, monocyte chemotaxis protein-1 (MCP-1), an HSC-responsive chemokine, was investigated in CF liver disease and biliary atresia. The bile-duct-ligated rat and in vitro coculture models of cholestatic liver injury were used to further explore the role of MCP-1 in HSC recruitment and proposed mechanism of induction via bile acids. In both CF liver disease and biliary atresia, elevated hepatic MCP-1 expression predominated in scar margin hepatocytes, closely associated with activated HSCs, and was also expressed in cholangiocytes. Serum MCP-1 was elevated during early fibrogenesis. Similar observations were made in bile-duct-ligated rat liver and serum. Hepatocytes isolated from cholestatic rats secreted increased MCP-1 which avidly recruited HSCs in coculture. This HSC chemotaxis was markedly inhibited in interventional studies using anti-MCP-1 neutralizing antibody. In CF liver disease, biliary MCP-1 was increased, positively correlating with levels of the hydrophobic bile acid, taurocholate. In cholestatic rats, increased MCP-1 positively correlated with taurocholate in serum and liver, and negatively correlated in bile. In normal human and rat hepatocytes, taurocholate induced MCP-1 expression. Conclusion: These observations support the hypothesis that up-regulation of hepatocyte-derived MCP-1, induced by bile acids, results in HSC recruitment in diverse causes of cholestatic liver injury, and is a key early event in liver fibrogenesis in these conditions. Therapies aimed at neutralizing MCP-1 or bile acids may help reduce fibro-obliterative liver injury in childhood cholestatic diseases. (HEPATOLOGY 2009;49:533-544.)
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