{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T13:29:07Z","timestamp":1754486947546,"version":"3.30.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1339,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,1]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>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)\u20131 and \u20132 in the progression of BA. The expression levels of HAI\u20131 and \u20132 were significantly increased in BA livers compared with those in neonatal hepatitis and correlated with disease progression. In BA livers, HAI\u20131 and \u20132 were coexpressed in cells involved in ductular reactions. In other selective cholangiopathies, ductular cells positive for HAI\u20131 or HAI\u20132 also increased in number. Inflammatory cytokines, growth factors, and bile acids differentially up\u2013regulated expression of HAI\u20131 and \u20132 transcripts in fetal liver cells and this induction could be antagonized by a cyclooxygenase\u20132 inhibitor. Conditioned media from cell lines stably overexpressing HAI\u20131 or HAI\u20132 enhanced the fibrogenic activity of portal fibroblasts and stellate cells, suggesting that both proteins might be involved in liver fibrosis. Because HAI\u20131 and \u20132 colocalized in ductular reactions sharing similar features to those observed during normal liver development, we sought to investigate the role of HAI\u20131 and \u20132 in cholangiopathies by exploring their functions in fetal liver cells. Knockdown of HAI\u20131 or HAI\u20132 promoted bidirectional differentiation of hepatoblast\u2013derived cells. In addition, we showed that the hepatocyte growth factor activator, mitogen\u2013activated protein kinase kinase 1, and phosphatidylinositol 3\u2013kinase signaling pathways were involved in hepatic differentiation enhanced by HAI\u20132 knockdown.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion\n                                 <\/jats:bold>\n                                 <jats:bold>: HAI\u20131 and \u20132 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. (Hepatology 2012)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.24657","type":"journal-article","created":{"date-parts":[[2011,9,2]],"date-time":"2011-09-02T18:45:40Z","timestamp":1314989140000},"page":"161-172","update-policy":"http:\/\/dx.doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":13,"title":["Persistent Elevation of Hepatocyte Growth Factor Activator Inhibitors in Cholangiopathies Affects Liver Fibrosis and 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