{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:38:40Z","timestamp":1793306320153,"version":"4.5.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T00:00:00Z","timestamp":1542067200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T00:00:00Z","timestamp":1542067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:p>High\u2010mobility group box\u20101 (HMGB1) is a damage\u2010associated molecular pattern (DAMP) increased in response to liver injury. Because HMGB1 is a ligand for the receptor for advanced glycation endproducts (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis though RAGE cell\u2010specific signaling mechanisms. Liver HMGB1 protein expression correlated with fibrosis stage in patients with chronic hepatitis C virus (HCV) infection, primary biliary cirrhosis (PBC), or alcoholic steatohepatitis (ASH). Hepatic HMGB1 protein expression and secretion increased in five mouse models of liver fibrosis attributed to drug\u2010induced liver injury (DILI), cholestasis, ASH, or nonalcoholic steatohepatitis (NASH). HMGB1 was up\u2010regulated and secreted mostly by hepatocytes and Kupffer cells (KCs) following CCl<jats:sub>4<\/jats:sub> treatment. Neutralization of HMGB1 protected, whereas injection of recombinant HMGB1 promoted liver fibrosis. <jats:italic toggle=\"yes\">Hmgb1<\/jats:italic> ablation in hepatocytes (<jats:italic toggle=\"yes\">Hmgb1<\/jats:italic>\n                           <jats:sup>\u0394Hep<\/jats:sup>) or in myeloid cells (<jats:italic toggle=\"yes\">Hmgb1<\/jats:italic>\n                           <jats:sup>\u0394Mye<\/jats:sup>) partially protected, whereas ablation in both (<jats:italic toggle=\"yes\">Hmgb1<\/jats:italic>\n                           <jats:sup>\u0394Hep\u0394Mye<\/jats:sup>) prevented liver fibrosis <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. Coculture with hepatocytes or KCs from CCl<jats:sub>4<\/jats:sub>\u2010injected wild\u2010type (WT) mice up\u2010regulated Collagen type I production by hepatic stellate cells (HSCs); yet, coculture with hepatocytes from CCl<jats:sub>4<\/jats:sub>\u2010injected <jats:italic toggle=\"yes\">Hmgb1<\/jats:italic>\n                           <jats:sup>\u0394Hep<\/jats:sup> or with KCs from CCl<jats:sub>4<\/jats:sub>\u2010injected <jats:italic toggle=\"yes\">Hmgb1<\/jats:italic>\n                           <jats:sup>\u0394Mye<\/jats:sup> mice partially blunted this effect. <jats:italic toggle=\"yes\">Rage<\/jats:italic> ablation in HSCs (<jats:italic toggle=\"yes\">Rage<\/jats:italic>\n                           <jats:sup>\u0394HSC<\/jats:sup>) and RAGE neutralization prevented liver fibrosis. Last, we identified that HMGB1 stimulated HSC migration and signaled through RAGE to up\u2010regulate Collagen type I expression by activating the phosphorylated mitogen\u2010activated protein kinase kinase (pMEK)1\/2, phosphorylated extracellular signal\u2010regulated kinase (pERK)1\/2 and pcJun signaling pathway. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Hepatocyte and KC\u2010derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling through RAGE in HSCs to activate the pMEK1\/2, pERK1\/2 and pcJun pathway and increase Collagen type I deposition.<\/jats:p>","DOI":"10.1002\/hep.30093","type":"journal-article","created":{"date-parts":[[2018,5,18]],"date-time":"2018-05-18T08:46:15Z","timestamp":1526633175000},"page":"2380-2404","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":137,"title":["High Mobility Group Box\u20101 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice"],"prefix":"10.1097","volume":"68","author":[{"given":"Xiaodong","family":"Ge","sequence":"first","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL"},{"name":"Division of Liver Diseases, Department of Medicine,Icahn School of Medicine at Mount Sinai,New York,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Arriazu","sequence":"additional","affiliation":[{"name":"Division of Liver Diseases, Department of Medicine,Icahn School of Medicine at Mount Sinai,New York,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Magdaleno","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Antoine","sequence":"additional","affiliation":[{"name":"MRC Centre for Inflammation Research, Queen\u2019s Medical Research Institute,University of Edinburgh,Edinburgh,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rouchelle","family":"dela Cruz","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Mount Sinai Beth Israel Medical Center,New York,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Theise","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Mount Sinai Beth Israel Medical Center,New York,NY"},{"name":"Department of Pathology,New York University Langone Medical Center,New York,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Nieto","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL"},{"name":"Division of Liver Diseases, Department of Medicine,Icahn School of Medicine at Mount Sinai,New York,NY"},{"name":"Department of Medicine, Division of Gastroenterology and 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