{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T13:45:03Z","timestamp":1778593503093,"version":"3.51.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"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":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Human NAFLD is characterized at early stages by hepatic steatosis, which may progress to NASH when the liver displays microvesicular steatosis, lobular inflammation, and pericellular fibrosis. The secretin (SCT)\/secretin receptor (SCTR) axis promotes biliary senescence and liver fibrosis in cholestatic models through down\u2010regulation of miR\u2010125b signaling. We aim to evaluate the effect of disrupting biliary SCT\/SCTR\/miR\u2010125b signaling on hepatic steatosis, biliary senescence, and liver fibrosis in NAFLD\/NASH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>\n                                 <jats:italic toggle=\"yes\">In vivo,<\/jats:italic> 4\u2010week\u2010old male wild\u2010type, <jats:italic toggle=\"yes\">Sct<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic toggle=\"yes\">Sctr<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice were fed a control diet or high\u2010fat diet (HFD) for 16 weeks. The expression of SCT\/SCTR\/miR\u2010125b axis was measured in human NAFLD\/NASH liver samples and HFD mouse livers by immunohistochemistry and quantitative PCR. Biliary\/hepatocyte senescence, ductular reaction, and liver angiogenesis were evaluated in mouse liver and human NAFLD\/NASH liver samples. miR\u2010125b target lipogenesis genes in hepatocytes were screened and validated by custom RT<jats:sup>2<\/jats:sup> Profiler PCR array and luciferase assay. Biliary SCT\/SCTR expression was increased in human NAFLD\/NASH samples and in livers of HFD mice, whereas the expression of miR\u2010125b was decreased. Biliary\/hepatocyte senescence, ductular reaction, and liver angiogenesis were observed in human NAFLD\/NASH samples as well as HFD mice, which were decreased in <jats:italic toggle=\"yes\">Sct<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic toggle=\"yes\">Sctr<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> HFD mice. <jats:italic toggle=\"yes\">Elovl1<\/jats:italic> is a lipogenesis gene targeted by miR\u2010125b, and its expression was also decreased in HFD mouse hepatocytes following <jats:italic toggle=\"yes\">Sct<\/jats:italic> or <jats:italic toggle=\"yes\">Sctr<\/jats:italic> knockout. Bile acid profile in fecal samples have the greatest changes between wild\u2010type mice and <jats:italic toggle=\"yes\">Sct<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup>\/<jats:italic toggle=\"yes\">Sctr<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The biliary SCT\/SCTR\/miR\u2010125b axis promotes liver steatosis by up\u2010regulating lipid biosynthesis gene <jats:italic toggle=\"yes\">Elovl1<\/jats:italic>. Targeting the biliary SCT\/SCTR\/miR\u2010125b axis may be key for ameliorating phenotypes of human NAFLD\/NASH.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31871","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T03:47:23Z","timestamp":1619754443000},"page":"1845-1863","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":29,"title":["Inhibition of Secretin\/Secretin Receptor Axis Ameliorates NAFLD Phenotypes"],"prefix":"10.1097","volume":"74","author":[{"given":"Lixian","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University,Indianapolis,IN"},{"name":"Richard L. 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