Premium
Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation
Author(s) -
Huang HsiangPo,
Chang MeiHwei,
Chen YiTzu,
Hsu HongYuan,
Chiang ChengLun,
Cheng TaiShan,
Wu YaoMing,
Wu Mu Zon,
Hsu YuChen,
Shen ChihChe,
Lee ChunNan,
Chuang YaHui,
Hong ChiaLun,
Jeng YungMing,
Chen PinHsun,
Chen HueyLing,
Lee MingShyue
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24657
Subject(s) - hepatocyte growth factor , biology , cancer research , medicine , hepatic stellate cell , endocrinology , hepatocyte , growth factor , fibrosis , biochemistry , receptor , in vitro
Alteration of cell surface proteolysis has been proposed to play a role in liver fibrosis, a grave complication of biliary atresia (BA). In this study we investigated the roles of hepatocyte growth factor activator inhibitor (HAI)‐1 and ‐2 in the progression of BA. The expression levels of HAI‐1 and ‐2 were significantly increased in BA livers compared with those in neonatal hepatitis and correlated with disease progression. In BA livers, HAI‐1 and ‐2 were coexpressed in cells involved in ductular reactions. In other selective cholangiopathies, ductular cells positive for HAI‐1 or HAI‐2 also increased in number. Inflammatory cytokines, growth factors, and bile acids differentially up‐regulated expression of HAI‐1 and ‐2 transcripts in fetal liver cells and this induction could be antagonized by a cyclooxygenase‐2 inhibitor. Conditioned media from cell lines stably overexpressing HAI‐1 or HAI‐2 enhanced the fibrogenic activity of portal fibroblasts and stellate cells, suggesting that both proteins might be involved in liver fibrosis. Because HAI‐1 and ‐2 colocalized in ductular reactions sharing similar features to those observed during normal liver development, we sought to investigate the role of HAI‐1 and ‐2 in cholangiopathies by exploring their functions in fetal liver cells. Knockdown of HAI‐1 or HAI‐2 promoted bidirectional differentiation of hepatoblast‐derived cells. In addition, we showed that the hepatocyte growth factor activator, mitogen‐activated protein kinase kinase 1, and phosphatidylinositol 3‐kinase signaling pathways were involved in hepatic differentiation enhanced by HAI‐2 knockdown. Conclusion : HAI‐1 and ‐2 are overexpressed in the liver in cholangiopathies with ductular reactions and are possibly involved in liver fibrosis and hepatic differentiation; they could be investigated as disease markers and potential therapeutic targets. (H epatology 2012)