{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:15:59Z","timestamp":1791324959909,"version":"4.3.1"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"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":[[2016,9]]},"abstract":"<jats:p>The secretin\/secretin receptor (SR) axis is up\u2010regulated by proliferating cholangiocytes during cholestasis. Secretin stimulates biliary proliferation by down\u2010regulation of let\u20107a and subsequent up\u2010regulation of the growth\u2010promoting factor, nerve growth factor (NGF). It is not known whether the secretin\/SR axis plays a role in subepithelial fibrosis observed during cholestasis. Our aim was to determine the role of the secretin\/SR axis in activation of biliary fibrosis in animal models and human primary sclerosing cholangitis (PSC). Studies were performed in wild\u2010type (WT) mice with bile duct ligation (BDL), BDL SR<jats:sup>\u2212\/\u2212<\/jats:sup> mice, or Mdr2<jats:sup>\u2212\/\u2212<\/jats:sup> mouse models of cholestatic liver injury. In selected studies, the SR antagonist (Sec 5\u201027) was used to block the secretin\/SR axis. Biliary proliferation and fibrosis were evaluated as well as secretion of secretin (by cholangiocytes and S cells), expression of markers of fibrosis, transforming growth factor\u2010\u03b21 (TGF\u2010\u03b21), transforming growth factor\u2010\u03b21 receptor (TGF\u2010\u03b21R), let\u20107a, and downstream expression of NGF. Correlative studies were performed in human control and PSC liver tissue biopsies, serum, and bile. SR antagonist reduced biliary proliferation and hepatic fibrosis in BDL WT and Mdr2<jats:sup>\u2212\/\u2212<\/jats:sup> mice. There was decreased expression of let\u20107a in BDL and Mdr2<jats:sup>\u2212\/\u2212<\/jats:sup> cholangiocytes that was associated with increased NGF expression. Inhibition of let\u20107a accelerated liver fibrosis was attributed to cholestasis. There was increased expression of TGF\u2010\u03b21 and TGF\u2010\u03b21R. Significantly higher expression of secretin, SR, and TGF\u2010\u03b21 was observed in PSC patient liver samples compared to healthy controls. In addition, there was higher expression of fibrosis genes and remarkably decreased expression of let\u20107a and increased expression of NGF compared to the control. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: The secretin\/SR axis plays a key role in regulating the biliary contribution to cholestasis\u2010induced hepatic fibrosis. (H<jats:sc>epatology<\/jats:sc> 2016;64:865\u2010879)<\/jats:p>","DOI":"10.1002\/hep.28622","type":"journal-article","created":{"date-parts":[[2016,4,27]],"date-time":"2016-04-27T11:44:43Z","timestamp":1461757483000},"page":"865-879","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":91,"title":["The secretin\/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor\u2010\u03b21 biliary secretion in mice"],"prefix":"10.1097","volume":"64","author":[{"given":"Nan","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Medicine and Medical Physiology,Texas A&M Health Science Center,College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyin","family":"Meng","sequence":"additional","affiliation":[{"name":"Research, Central Texas Veterans Health Care System,Temple,TX"},{"name":"Scott & White Digestive Disease Research Center,Scott & White,Temple,TX"},{"name":"Operational Funds,Baylor Scott & White,Temple,TX"},{"name":"Department of Medicine and Medical Physiology,Texas A&M Health Science Center,College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Invernizzi","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center,Rozzano,Milan,Italy"},{"name":"Program for Autoimmune Liver Diseases,International Center for Digestive Health,Department of Medicine and Surgery,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bernuzzi","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center,Rozzano,Milan,Italy"},{"name":"Program for Autoimmune Liver Diseases,International Center for Digestive Health,Department of Medicine and Surgery,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Venter","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Physiology,Texas A&M Health Science Center,College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Standeford","sequence":"additional","affiliation":[{"name":"Research, Central Texas Veterans Health Care System,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Onori","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences,La Sapienza,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Marzioni","sequence":"additional","affiliation":[{"name":"Department of Medicine,Universita' Politecnica delle Marche,Ancona,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Alvaro","sequence":"additional","affiliation":[{"name":"Department of Medico\u2010Surgical Sciences and Biotechnologies,Polo Pontino,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Franchitto","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences,La Sapienza,Rome,Italy"},{"name":"Eleonora Lorillard Spencer Cenci Foundation,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences,La Sapienza,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[{"name":"Research, Central Texas Veterans Health Care System,Temple,TX"},{"name":"Scott & White Digestive Disease Research Center,Scott & White,Temple,TX"},{"name":"Department of Medicine and Medical Physiology,Texas A&M Health Science Center,College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Alpini","sequence":"additional","affiliation":[{"name":"Research, Central Texas Veterans Health Care System,Temple,TX"},{"name":"Scott & White Digestive Disease Research Center,Scott & White,Temple,TX"},{"name":"Department of Medicine and Medical Physiology,Texas A&M Health Science Center,College of Medicine,Temple,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2016,6,11]]},"reference":[{"key":"hep28622-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1172\/JCI113355","article-title":"Biliary physiology in rats with bile ductular cell hyperplasia. 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