{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T05:57:04Z","timestamp":1769839024465,"version":"3.49.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T00:00:00Z","timestamp":1581638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T00:00:00Z","timestamp":1581638400000},"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":[[2020,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Bile acids (BAs) are important regulators of metabolism and energy balance, but excess BAs cause cholestatic liver injury. The histone methyltransferase mixed\u2010lineage leukemia\u20104 (MLL4) is a transcriptional coactivator of the BA\u2010sensing nuclear receptor farnesoid X receptor (FXR) and epigenetically up\u2010regulates FXR targets important for the regulation of BA levels, small heterodimer partner (SHP), and bile salt export pump (BSEP). MLL4 expression is aberrantly down\u2010regulated and BA homeostasis is disrupted in cholestatic mice, but the underlying mechanisms are unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      We examined whether elevated microRNA\u2010210 (miR\u2010210) in cholestatic liver promotes BA\u2010induced pathology by inhibiting MLL4 expression. miR\u2010210 was the most highly elevated miR in hepatic SHP\u2010down\u2010regulated mice with elevated hepatic BA levels. MLL4 was identified as a direct target of miR\u2010210, and overexpression of miR\u2010210 inhibited MLL4 and, subsequently, BSEP and SHP expression, resulting in defective BA metabolism and hepatotoxicity with inflammation. miR\u2010210 levels were elevated in cholestatic mouse models, and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      silencing of miR\u2010210 ameliorated BA\u2010induced liver pathology and decreased hydrophobic BA levels in an MLL4\u2010dependent manner. In gene expression studies, SHP inhibited\n                      <jats:italic toggle=\"yes\">miR\u2010210<\/jats:italic>\n                      expression by repressing a transcriptional activator, Kruppel\u2010like factor\u20104 (KLF4). In patients with primary biliary cholangitis\/cirrhosis (PBC), hepatic levels of miR\u2010210 and KLF4 were highly elevated, whereas nuclear levels of SHP and MLL4 were reduced.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hepatic miR\u2010210 is physiologically regulated by SHP but elevated in cholestatic mice and patients with PBC, promoting BA\u2010induced liver injury in part by targeting MLL4. The miR\u2010210\u2013MLL4 axis is a potential target for the treatment of BA\u2010associated hepatobiliary disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.30966","type":"journal-article","created":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T06:33:44Z","timestamp":1569306824000},"page":"2118-2134","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":34,"title":["MicroRNA\u2010210 Promotes Bile Acid\u2013Induced Cholestatic Liver Injury by Targeting Mixed\u2010Lineage Leukemia\u20104 Methyltransferase in Mice"],"prefix":"10.1097","volume":"71","author":[{"given":"Young\u2010Chae","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology,University of Illinois at Urbana\u2010Champaign,Urbana,IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunkyung","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology,University of Illinois at Urbana\u2010Champaign,Urbana,IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunmi","family":"Seok","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology,University of Illinois at Urbana\u2010Champaign,Urbana,IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Computational Biology Department,School of Computer Science,Carnegie Mellon University,Pittsburgh,PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Ma","sequence":"additional","affiliation":[{"name":"Computational Biology Department,School of Computer Science,Carnegie Mellon University,Pittsburgh,PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiangang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Toxicology and Therapeutics,Kansas University Medical Center,Kansas City,KS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byron","family":"Kemper","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology,University of Illinois at Urbana\u2010Champaign,Urbana,IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jongsook Kim","family":"Kemper","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology,University of Illinois at Urbana\u2010Champaign,Urbana,IL"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2020,2,14]]},"reference":[{"key":"hep30966-bib-0001-20260126","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/j.2040-4603.2013.tb00517.x","article-title":"Bile acid metabolism and signaling","volume":"3","year":"2013","journal-title":"Compr 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