{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T03:08:52Z","timestamp":1789441732000,"version":"build-2803163510"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T00:00:00Z","timestamp":1642809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T00:00:00Z","timestamp":1642809600000},"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":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Iron overload (IO) is a frequent finding in the general population. As the major iron storage site, the liver is subject to iron toxicity. Farnesoid X receptor (FXR) regulates bile acid metabolism and is implicated in various liver diseases. We aimed to determine whether FXR plays a role in regulating iron hepatotoxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      Human and mouse hepatocytes were treated with ferric ammonium citrate or iron dextran (FeDx). Mice were orally administered ferrous sulfate or injected i.p. with FeDx. Wild\u2010type and\n                      <jats:italic toggle=\"yes\">Fxr\u2212\/\u2212<\/jats:italic>\n                      mice were fed an iron\u2010rich diet for 1 or 5 weeks. Mice fed an iron\u2010rich diet were coadministered the FXR agonist, GW4064. Forced expression of FXR was carried out with recombinant adeno\u2010associated virus 1 week before iron\u2010rich diet feeding. Serum levels of bile acids and fibroblast growth factor 19 (FGF19) were quantified in adults with hyperferritinemia and children with \u03b2\u2010thalassemia. The data demonstrated that iron suppressed FXR expression and signaling in human and mouse hepatocytes as well as in mouse liver and intestine. FXR deficiency potentiated iron hepatotoxicity, accompanied with hepatic steatosis as well as dysregulated iron and bile acid homeostasis. FXR negatively regulated iron\u2010regulatory proteins 1 and 2 and prevented hepatic iron accumulation. Forced FXR expression and ligand activation significantly suppressed iron hepatotoxicity in iron\u2010fed mice. The FXR agonist, GW4064, almost completely restored dysregulated bile acid signaling and metabolic syndrome in iron\u2010fed mice. Conjugated primary bile acids were increased and FGF19 was decreased in serum of adults with hyperferritinemia and children with \u03b2\u2010thalassemia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>FXR plays a pivotal role in regulating iron homeostasis and protects mice against iron hepatotoxicity. Targeting FXR may represent a therapeutic strategy for IO\u2010associated chronic liver diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32270","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T09:14:22Z","timestamp":1638782062000},"page":"387-403","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":39,"title":["Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron\u2010induced hepatotoxicity"],"prefix":"10.1097","volume":"76","author":[{"given":"Hui","family":"Xiong","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science and Technology,Tianjin University,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunze","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery,Tianjin Union Medical Center,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifeng","family":"Han","sequence":"additional","affiliation":[{"name":"Tianjin State Key Laboratory of Modern Chinese Medicine,Tianjin Key Laboratory of TCM Chemistry and Analysis,Tianjin University of Traditional Chinese Medicine,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science and Technology,Tianjin University,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khawar","family":"Saeed","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science and Technology,Tianjin University,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Han","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science and Technology,Tianjin University,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science and Technology,Tianjin University,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis D.","family":"Klaassen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,Kansas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism,Center for Cancer Research,National Cancer Institute,NIH,Bethesda,Maryland,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfu","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,Zunyi Medical University,Zunyi,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youcai","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science and Technology,Tianjin University,Tianjin,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,1,22]]},"reference":[{"key":"hep32270-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1152\/physrev.00008.2013","article-title":"Systemic iron homeostasis","volume":"93","year":"2013","journal-title":"Physiol Rev"},{"key":"hep32270-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.12659\/MSM.896494","article-title":"The role of iron and iron overload in chronic liver disease","volume":"22","year":"2016","journal-title":"Med Sci 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