https://scholars.lib.ntu.edu.tw/handle/123456789/439024
標題: | Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation | 作者: | HSIANG-PO HUANG MEI-HWEI CHANG Chen Y.-T. HONG-YUAN HSU Chiang C.-L. Cheng T.-S. YAO-MING WU MU-ZON WU Hsu Y.-C. Shen C.-C. Lee C.-N. YA-HUI CHUANG Hong C.-L. YUNG-MING JENG Chen P.-H. HUEY-LING CHEN MING-SHYUE LEE |
公開日期: | 2012 | 卷: | 55 | 期: | 1 | 起(迄)頁: | 161-172 | 來源出版物: | Hepatology | 摘要: | 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://www.scopus.com/inward/record.uri?eid=2-s2.0-84155195023&doi=10.1002%2fhep.24657&partnerID=40&md5=86326894ae77458f22dd588127a62d28 https://scholars.lib.ntu.edu.tw/handle/123456789/439024 |
ISSN: | 0270-9139 | DOI: | 10.1002/hep.24657 | SDG/關鍵字: | 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 |
顯示於: | 醫學教育暨生醫倫理學科所 |
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