{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:07:35Z","timestamp":1790507255558,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2017,8,26]],"date-time":"2017-08-26T00:00:00Z","timestamp":1503705600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,8,26]],"date-time":"2017-08-26T00:00:00Z","timestamp":1503705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:p>\n                    Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic long noncoding RNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of\n                    <jats:italic toggle=\"yes\">H19<\/jats:italic>\n                    RNA augmented bile duct ligation (BDL)\u2010induced liver fibrosis, which was accompanied by the elevation of serum alanine aminotransferase, aspartate aminotransferase, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19\u2010BDL versus null\u2010BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19\u2010BDL mice showed significant enrichment of CD3+\u03b3\u03b4+, interleukin\u20104, and interleukin\u201017 producing CD4+ and CD8+ immune cell populations. H19 down\u2010regulated hepatic zinc finger E\u2010box\u2010binding homeobox 1 (ZEB1) but up\u2010regulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)\u2010box 9 expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription.\n                    <jats:italic toggle=\"yes\">H19<\/jats:italic>\n                    RNA impeded ZEB1's inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19\u2010induced fibrosis; the latter was also prevented in\n                    <jats:italic toggle=\"yes\">H19<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice.\n                    <jats:italic toggle=\"yes\">H19<\/jats:italic>\n                    RNA was markedly induced by bile acids in mouse small cholangiocytes and to a lesser extent in mouse large cholangiocytes. The up\u2010regulation of\n                    <jats:italic toggle=\"yes\">H19<\/jats:italic>\n                    RNA and EpCAM correlated positively with the down\u2010regulation of ZEB1 in primary sclerosing cholangitis and primary biliary cirrhosis liver specimens.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    The activation of hepatic\n                    <jats:italic toggle=\"yes\">H19<\/jats:italic>\n                    RNA promoted cholestatic liver fibrosis in mice through the ZEB1\/EpCAM signaling pathway. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2017;66:1183\u20101196).\n                  <\/jats:p>","DOI":"10.1002\/hep.29209","type":"journal-article","created":{"date-parts":[[2017,4,13]],"date-time":"2017-04-13T14:29:57Z","timestamp":1492093797000},"page":"1183-1196","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":138,"title":["H19 promotes cholestatic liver fibrosis by preventing ZEB1\u2010mediated inhibition of epithelial cell adhesion molecule"],"prefix":"10.1097","volume":"66","author":[{"given":"Yongfeng","family":"Song","sequence":"first","affiliation":[{"name":"Department of Physiology and Neurobiology,and Institute for Systems Genomics, University of Connecticut,Storrs,CT"},{"name":"Department of Endocrinology and Metabolism,Shandong Provincial Hospital affiliated to Shandong University,Jinan,Shandong,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chune","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology,and Institute for Systems Genomics, University of Connecticut,Storrs,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases,Allergy & Immunology, Saint Louis University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Trottier","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology,CHU\u2010Qu\u00e9bec Research Centre and Faculty of Pharmacy, Laval University,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Beaudoin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology,and Institute for Systems Genomics, University of Connecticut,Storrs,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology,and Institute for Systems Genomics, University of Connecticut,Storrs,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Pope","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences,School of Pharmacy, University of Connecticut,Storrs,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyong","family":"Peng","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases,Allergy & Immunology, Saint Louis University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Barbier","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology,CHU\u2010Qu\u00e9bec Research Centre and Faculty of Pharmacy, Laval University,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences,School of Pharmacy, University of Connecticut,Storrs,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linheng","family":"Li","sequence":"additional","affiliation":[{"name":"Stowers Institute for Medical Research,Kansas City,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology,and Institute for Systems Genomics, University of Connecticut,Storrs,CT"},{"name":"Department of Internal Medicine,Section of Digestive Diseases, Yale University,New Haven,CT"},{"name":"Veterans Affairs Connecticut Healthcare System,West Haven,CT"},{"name":"School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,Zhejiang,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,8,26]]},"reference":[{"key":"hep29209-bib-0001-20250714","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/S1534-5807(02)00187-9","article-title":"Redundant pathways for negative feedback regulation of bile acid production","volume":"2","year":"2002","journal-title":"Dev Cell"},{"key":"hep29209-bib-0002-20250714","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1194\/jlr.R900010-JLR200","article-title":"Bile acids: regulation of synthesis","volume":"50","year":"2009","journal-title":"J Lipid Res"},{"key":"hep29209-bib-0003-20250714","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/hep.27121","article-title":"E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr\u20101\/SHP\/EID1 network","volume":"60","year":"2014","journal-title":"Hepatology"},{"key":"hep29209-bib-0004-20250714","doi-asserted-by":"crossref","first-page":"171","DOI":"10.5603\/FHC.2012.0026","article-title":"Igf2\u2010H19, an imprinted tandem gene, is an important regulator of embryonic development, a guardian of proliferation of adult pluripotent stem cells, a regulator of longevity, and a \u201cpasskey\u201d to cancerogenesis","volume":"50","year":"2012","journal-title":"Folia Histochem Cytobiol"},{"key":"hep29209-bib-0005-20250714","doi-asserted-by":"crossref","first-page":"20559","DOI":"10.1038\/srep20559","article-title":"Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function","volume":"6","year":"2016","journal-title":"Sci Rep"},{"key":"hep29209-bib-0006-20250714","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/ncb1722","article-title":"The miR\u2010200 family and miR\u2010205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1","volume":"10","year":"2008","journal-title":"Nat Cell Biol"},{"key":"hep29209-bib-0007-20250714","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1172\/JCI76725","article-title":"ZEB1 drives epithelial\u2010to\u2010mesenchymal transition in lung cancer","volume":"126","year":"2016","journal-title":"J Clin Invest"},{"key":"hep29209-bib-0008-20250714","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.bbrc.2011.11.011","article-title":"Regulation of miR\u2010200c by nuclear receptors PPARalpha, LRH\u20101 and SHP","volume":"416","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"key":"hep29209-bib-0009-20250714","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.bbadis.2010.10.006","article-title":"Role of nuclear receptor SHP in metabolism and cancer","volume":"1812","year":"2011","journal-title":"Biochim Biophys Acta"},{"key":"hep29209-bib-0010-20250714","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1146\/annurev-pharmtox-010715-103209","article-title":"nuclear receptors as therapeutic targets in liver disease: are we there yet?","volume":"56","year":"2016","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"hep29209-bib-0011-20250714","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.18632\/oncotarget.6387","article-title":"The role of the oncofetal H19 lncRNA in tumor metastasis: orchestrating the EMT\u2010MET decision","volume":"7","year":"2016","journal-title":"Oncotarget"},{"key":"hep29209-bib-0012-20250714","doi-asserted-by":"crossref","first-page":"G233","DOI":"10.1152\/ajpgi.00069.2014","article-title":"EpCAM and the biology of hepatic stem\/progenitor cells","volume":"308","year":"2015","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep29209-bib-0013-20250714","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.jhep.2016.05.022","article-title":"EpCAM\u2010regulated intramembrane proteolysis induces a cancer stem cell\u2010like gene signature in hepatitis B virus\u2010infected hepatocytes","volume":"65","year":"2016","journal-title":"J Hepatol"},{"key":"hep29209-bib-0014-20250714","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/ncb1824","article-title":"Nuclear signalling by tumour\u2010associated antigen EpCAM","volume":"11","year":"2009","journal-title":"Nat Cell Biol"},{"key":"hep29209-bib-0015-20250714","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/toxsci\/kfs342","article-title":"Molecular mechanisms of fibrosis\u2010associated promotion of liver carcinogenesis","volume":"132","year":"2013","journal-title":"Toxicol Sci"},{"key":"hep29209-bib-0016-20250714","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nature12303","article-title":"Maternal imprinting at the H19\u2010Igf2 locus maintains adult haematopoietic stem cell quiescence","volume":"500","year":"2013","journal-title":"Nature"},{"key":"hep29209-bib-0017-20250714","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/hep.27437","article-title":"Small heterodimer partner\/neuronal PAS domain protein 2 axis regulates the oscillation of liver lipid metabolism","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep29209-bib-0018-20250714","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1016\/j.ajpath.2016.07.014","article-title":"REV\u2010ERBalpha activates C\/EBP homologous protein to control small heterodimer partner\u2010mediated oscillation of alcoholic fatty liver","volume":"186","year":"2016","journal-title":"Am J Pathol"},{"key":"hep29209-bib-0019-20250714","doi-asserted-by":"crossref","first-page":"E961","DOI":"10.1152\/ajpendo.00655.2009","article-title":"Overexpression of nuclear receptor SHP in adipose tissues affects diet\u2010induced obesity and adaptive thermogenesis","volume":"298","year":"2010","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"hep29209-bib-0020-20250714","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1002\/hep.28882","article-title":"Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep29209-bib-0021-20250714","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.febslet.2011.03.059","article-title":"Nuclear receptor SHP inhibition of Dnmt1 expression via ERRgamma","volume":"585","year":"2011","journal-title":"FEBS Lett"},{"key":"hep29209-bib-0022-20250714","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1158\/1535-7163.MCT-16-0153","article-title":"A novel small molecule activator of nuclear receptor SHP inhibits HCC cell migration via suppressing Ccl2","volume":"15","year":"2016","journal-title":"Mol Cancer Ther"},{"key":"hep29209-bib-0023-20250714","doi-asserted-by":"crossref","first-page":"24871","DOI":"10.1074\/jbc.M110.133280","article-title":"Novel polymorphisms of nuclear receptor SHP associated with functional and structural changes","volume":"285","year":"2010","journal-title":"J Biol Chem"},{"key":"hep29209-bib-0024-20250714","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.febslet.2012.03.022","article-title":"An autoregulatory feedback loop between Mdm2 and SHP that fine tunes Mdm2 and SHP stability","volume":"586","year":"2012","journal-title":"FEBS Lett"},{"key":"hep29209-bib-0025-20250714","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1002\/hep.23883","article-title":"Adenosine triphosphate release and purinergic (P2) receptor\u2010mediated secretion in small and large mouse cholangiocytes","volume":"52","year":"2010","journal-title":"Hepatology"},{"key":"hep29209-bib-0026-20250714","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/j.jhep.2016.02.024","article-title":"miR\u201034a\u2010dependent overexpression of Per1 decreases cholangiocarcinoma growth","volume":"64","year":"2016","journal-title":"J Hepatol"},{"key":"hep29209-bib-0027-20250714","doi-asserted-by":"crossref","first-page":"17462","DOI":"10.18632\/oncotarget.3958","article-title":"CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome","volume":"6","year":"2015","journal-title":"Oncotarget"},{"key":"hep29209-bib-0028-20250714","doi-asserted-by":"crossref","first-page":"e65256","DOI":"10.1371\/journal.pone.0065256","article-title":"A feedback inhibition between miRNA\u2010127 and TGFbeta\/c\u2010Jun cascade in HCC cell migration via MMP13","volume":"8","year":"2013","journal-title":"PLoS One"},{"key":"hep29209-bib-0029-20250714","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1053\/j.gastro.2015.01.045","article-title":"Interactions between nuclear receptor SHP and FOXA1 maintain oscillatory homocysteine homeostasis in mice","volume":"148","year":"2015","journal-title":"Gastroenterology"},{"key":"hep29209-bib-0030-20250714","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/hep.27035","article-title":"Mesodermal mesenchymal cells give rise to myofibroblasts, but not epithelial cells, in mouse liver injury","volume":"60","year":"2014","journal-title":"Hepatology"},{"key":"hep29209-bib-0031-20250714","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1002\/hep.24122","article-title":"Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem\/progenitor cells in humans","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep29209-bib-0032-20250714","doi-asserted-by":"crossref","first-page":"4850","DOI":"10.1093\/nar\/gks159","article-title":"Zinc\u2010induced Dnmt1 expression involves antagonism between MTF\u20101 and nuclear receptor SHP","volume":"40","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"hep29209-bib-0033-20250714","doi-asserted-by":"crossref","first-page":"28893","DOI":"10.1074\/jbc.M113.502682","article-title":"MicroRNA\u2010433 inhibits liver cancer cell migration by repressing the protein expression and function of cAMP response element\u2010binding protein","volume":"288","year":"2013","journal-title":"J Biol Chem"},{"key":"hep29209-bib-0034-20250714","first-page":"266","article-title":"Primary biliary cirrhosis and primary sclerosing cholangitis: a review featuring a women's health perspective","volume":"2","year":"2014","journal-title":"J Clin Transl Hepatol"},{"key":"hep29209-bib-0035-20250714","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1053\/j.gastro.2013.11.034","article-title":"Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion","volume":"146","year":"2014","journal-title":"Gastroenterology"},{"key":"hep29209-bib-0036-20250714","doi-asserted-by":"crossref","first-page":"e845","DOI":"10.1371\/journal.pone.0000845","article-title":"The H19 non\u2010coding RNA is essential for human tumor growth","volume":"2","year":"2007","journal-title":"PLoS One"},{"key":"hep29209-bib-0037-20250714","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1111\/his.12312","article-title":"Childhood hepatocellular carcinoma: a clinicopathological study of 12 cases with special reference to EpCAM","volume":"64","year":"2014","journal-title":"Histopathology"},{"key":"hep29209-bib-0038-20250714","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1016\/j.bbrc.2016.12.017","article-title":"ZEB1 is neither sufficient nor required for epithelial\u2010mesenchymal transition in LS174T colorectal cancer cells","volume":"482","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"hep29209-bib-0039-20250714","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1136\/gutjnl-2014-308176","article-title":"Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches","volume":"65","year":"2016","journal-title":"Gut"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29209","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201710000-00024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T07:00:47Z","timestamp":1752476447000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201710000-00024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,26]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29209","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.727503732.793540986","asserted-by":"object"}]},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,26]]},"assertion":[{"value":"2017-02-02","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-04-05","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}