{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T17:02:54Z","timestamp":1778432574526,"version":"3.51.4"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Ischemia\u2013reperfusion injury (IRI) represents a risk factor in liver transplantation (LT). We have shown that overexpression of heme oxygenase\u20101 (HO\u20101) mitigates hepatic IRI in LT recipients. Here, we hypothesized that human antigen R (HuR), the stabilizer of adenylate\u2010uridylate (AU)\u2010rich mRNAs, is required for hepatoprotection in LT.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>In an experimental arm, HuR\/HO\u20101 protein expression was correlated with hepatic IRI phenotype. In an <jats:italic toggle=\"yes\">in vitro<\/jats:italic> inflammation mimic model of hepatic warm IRI, induction of HuR\/HO\u20101 and cytoplasmic localization following cytokine preconditioning were detected in primary hepatocyte cultures, whereas HuR silencing caused negative regulation of HO\u20101, followed by enhanced cytotoxicity. Using the HuR\u2010inhibitor, we showed that HuR likely regulates HO\u20101 through its 3\u2032 untranslated region and causes neutrophil activation (CD69+\/lymphocyte antigen 6 complex locus G [Ly6\u2010G]). HuR silencing in bone marrow\u2013derived macrophages decreased HO\u20101 expression, leading to the induction of proinflammatory cytokines\/chemokines. RNA sequencing of HuR silenced transcripts under <jats:italic toggle=\"yes\">in vitro<\/jats:italic> warm IRI revealed regulation of genes <jats:italic toggle=\"yes\">thymus cell antigen 1 (THY1), aconitate decarboxylase 1 (ACOD1)<\/jats:italic>, and <jats:italic toggle=\"yes\">Prostaglandin E Synthase (PTGES)<\/jats:italic>. HuR, but not hypoxia\u2010inducible protein alpha, positively regulated HO\u20101 in warm, but not cold, hypoxia\/reoxygenation conditions. HuR modulated HO\u20101 in primary hepatocytes, neutrophils, and macrophages under reperfusion. Adjunctive inhibition of HuR diminished microtubule\u2010associated proteins 1A\/1B light chain 3B (LC3B), a marker for autophagosome, under HO\u20101 regulation, suggesting a cytoprotective mechanism in hepatic IR. In a clinical arm, hepatic biopsies from 51 patients with LT were analyzed at 2\u00a0hours after reperfusion. Graft HuR expression was negatively correlated with macrophage (CD80\/CD86) and neutrophil (Cathepsin G) markers. Hepatic IRI increased HuR\/HO\u20101 expression and inflammatory genes. High HuR\u2013expressing liver grafts showed lower serum alanine aminotransferase\/serum aspartate aminotransferase levels and improved LT survival.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This translational study identifies HuR as a regulator of HO\u20101\u2013mediated cytoprotection in sterile liver inflammation and a biomarker of ischemic stress resistance in LT.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31093","type":"journal-article","created":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T08:19:01Z","timestamp":1577434741000},"page":"1056-1072","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":23,"title":["Human Antigen R (HuR): A Regulator of Heme Oxygenase\u20101 Cytoprotection in Mouse and Human Liver Transplant Injury"],"prefix":"10.1097","volume":"72","author":[{"given":"Kenneth J.","family":"Dery","sequence":"first","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kojiro","family":"Nakamura","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"},{"name":"Department of Surgery,Kyoto University,Kyoto,Japan"},{"name":"Department of Surgery,Nishi\u2010Kobe Medical Center,Kobe,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Kadono","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Hirao","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoichi","family":"Kageyama","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Ito","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidenobu","family":"Kojima","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fady M.","family":"Kaldas","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of Medicine at UCLA,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8157-1531","authenticated-orcid":false,"given":"Ronald W.","family":"Busuttil","sequence":"additional","affiliation":[{"name":"The Dumont\u2010UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation,David Geffen School of 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