{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:56:29Z","timestamp":1791406589344,"version":"4.3.3"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T00:00:00Z","timestamp":1551657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T00:00:00Z","timestamp":1551657600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>\n                    Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ\u2019s function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha\u2010naphthyl\u2010isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up\u2010regulated. Importantly,\n                    <jats:italic toggle=\"yes\">Areg\u2013\/\u2013<\/jats:italic>\n                    mice showed aggravated liver injury after BDL and ANIT administration compared to\n                    <jats:italic toggle=\"yes\">Areg+\/+<\/jats:italic>\n                    mice. Recombinant AREG protected from ANIT and BDL\u2010induced liver injury and reduced BA\u2010triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic\n                    <jats:italic toggle=\"yes\">Areg<\/jats:italic>\n                    expression, and, interestingly, cholestyramine feeding reduced postprandial\n                    <jats:italic toggle=\"yes\">Areg<\/jats:italic>\n                    up\u2010regulation in both tissues. Most interestingly,\n                    <jats:italic toggle=\"yes\">Areg\u2013\/\u2013<\/jats:italic>\n                    mice displayed high hepatic cholesterol 7 \u03b1\u2010hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of\n                    <jats:italic toggle=\"yes\">Cyp7a1<\/jats:italic>\n                    was impaired in\n                    <jats:italic toggle=\"yes\">Areg\u2013\/\u2013<\/jats:italic>\n                    mice, and recombinant AREG down\u2010regulated\n                    <jats:italic toggle=\"yes\">Cyp7a1<\/jats:italic>\n                    mRNA in hepatocytes. On the other hand, BAs promoted\n                    <jats:italic toggle=\"yes\">AREG<\/jats:italic>\n                    gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in\n                    <jats:italic toggle=\"yes\">Fxr\u2013\/\u2013<\/jats:italic>\n                    mice, and involved EGFR transactivation. Finally, we show that hepatic\n                    <jats:italic toggle=\"yes\">EGFR<\/jats:italic>\n                    expression is indirectly induced by BA\u2010FXR through activation of suppressor of cytokine signaling\u20103 (SOC3).\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    AREG\u2010EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.\n                  <\/jats:p>","DOI":"10.1002\/hep.30348","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T02:08:30Z","timestamp":1541729310000},"page":"1632-1647","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":67,"title":["The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis"],"prefix":"10.1097","volume":"69","author":[{"given":"Eva","family":"Santamar\u00eda","sequence":"first","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"},{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos M.","family":"Rodr\u00edguez\u2010Ortigosa","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"},{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Instituto de Investigaciones Sanitarias de Navarra\u2010IdiSNA,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iker","family":"Uriarte","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"},{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria U.","family":"Latasa","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Urtasun","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Alvarez\u2010Sola","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"B\u00e1rcena\u2010Varela","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Colyn","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Arcelus","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalen","family":"Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Deutschmann","sequence":"additional","affiliation":[{"name":"Gastroenterology, Hepatology and Infectious Diseases Clinic,University Hospital D\u00fcsseldorf, Medical Faculty Heinrich\u2010Heine\u2010University,D\u00fcsseldorf,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Peleteiro\u2010Vigil","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM),IBSAL, University of Salamanca,Salamanca,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"G\u00f3mez\u2010Cambronero","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,Wright State University School of Medicine,Dayton,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Department of Medical Biology,Pomeranian Medical University,Szczecin,Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Milkiewicz","sequence":"additional","affiliation":[{"name":"Translational Medicine Group,Pomeranian Medical University,Szczecin,Poland"},{"name":"Liver and Internal Medicine Unit,Medical University of Warsaw,Warsaw,Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Sangro","sequence":"additional","affiliation":[{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Instituto de Investigaciones Sanitarias de Navarra\u2010IdiSNA,Pamplona,Spain"},{"name":"Hepatology Unit, Navarra University Clinic,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Keitel","sequence":"additional","affiliation":[{"name":"Gastroenterology, Hepatology and Infectious Diseases Clinic,University Hospital D\u00fcsseldorf, Medical Faculty Heinrich\u2010Heine\u2010University,D\u00fcsseldorf,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Monte","sequence":"additional","affiliation":[{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM),IBSAL, University of Salamanca,Salamanca,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose J.G.","family":"Marin","sequence":"additional","affiliation":[{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM),IBSAL, University of Salamanca,Salamanca,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maite G.","family":"Fern\u00e1ndez\u2010Barrena","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"},{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matias A.","family":"\u00c1vila","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"},{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Instituto de Investigaciones Sanitarias de Navarra\u2010IdiSNA,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Berasain","sequence":"additional","affiliation":[{"name":"Hepatology Program,University of Navarra,Cima,Pamplona,Spain"},{"name":"CIBERehd, Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Instituto de Investigaciones Sanitarias de Navarra\u2010IdiSNA,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,3,4]]},"reference":[{"key":"hep30348-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1053\/j.gastro.2010.09.004","article-title":"Pathogenesis of cholestatic liver disease and therapeutic approaches","volume":"139","year":"2010","journal-title":"Gastroenterology"},{"key":"hep30348-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/hep.28965","article-title":"The ascending pathophysiology of cholestatic liver disease","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep30348-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3748\/wjg.15.1677","article-title":"Bile\u2010acid\u2010induced cell injury and 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