|Title:||Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation||Authors:||Huang H.-P.
|Issue Date:||2012||Journal Volume:||55||Journal Issue:||1||Start page/Pages:||161-172||Source:||Hepatology||Abstract:||
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. ? 2011 American Association for the Study of Liver Diseases.
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/508299||ISSN:||0270-9139||DOI:||10.1002/hep.24657||metadata.dc.subject.other:||Aqp1 protein; carbamoyl phosphate synthase; celecoxib; cell protein; chenodeoxycholic acid; cholic acid; cyclooxygenase 2; cytokeratin 19; deoxycholic acid; hepatocyte growth factor activator; hepatocyte growth factor activator inhibitor 1; hepatocyte growth factor activator inhibitor 2; interleukin 1beta; lithocholic acid; messenger RNA; mitogen activated protein kinase 1; Notch1 receptor; phosphatidylinositol 3 kinase; proteinase; transactivator protein; transforming growth factor beta1; tumor necrosis factor alpha; unclassified drug; animal cell; animal experiment; animal model; article; bile duct atresia; bile duct disease; cell differentiation; cell lineage; controlled study; disease course; extracellular matrix; fetus; gene induction; gene overexpression; gene silencing; hepatic duct; human; human tissue; intracellular signaling; liver cell; liver development; liver fibrosis; mouse; newborn; newborn hepatitis; nonhuman; obstructive jaundice; priority journal; protein expression; protein induction; protein localization; rat; stem cell; upregulation; Animals; Cell Differentiation; Cell Line; Cholestasis; Female; Fibroblasts; Hepatic Stellate Cells; Hepatitis; Hepatocytes; Humans; Infant; Infant, Newborn; Liver Cirrhosis; Male; Membrane Glycoproteins; Membrane Proteins; Mice; Mice, Inbred C57BL; Proteinase Inhibitory Proteins, Secretory; Rats; Signal Transduction; Stem Cells
|Appears in Collections:||法醫學科所|
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