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Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic <jats:italic>LCN2<\/jats:italic> expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. <jats:italic>Lcn2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were protected from liver fibrosis caused by either ethanol or CCl<jats:sub>4<\/jats:sub> exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in <jats:italic>Lcn2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice exposed to CCl<jats:sub>4<\/jats:sub>, along with decrease in <jats:italic>Timp1<\/jats:italic> and <jats:italic>Edn1<\/jats:italic> expression. Hepatic expression of <jats:italic>COL1A1<\/jats:italic>, <jats:italic>TIMP1<\/jats:italic> and key <jats:italic>EDN1<\/jats:italic> system components were elevated in AH patients and correlated with hepatic <jats:italic>LCN2<\/jats:italic> expressio<jats:italic>n.<\/jats:italic> In vitro<jats:italic>,<\/jats:italic> recombinant LCN2 induced <jats:italic>COL1A1<\/jats:italic> expression. Overexpression of <jats:italic>LCN2<\/jats:italic> increased HIF1A that in turn mediated <jats:italic>EDN1<\/jats:italic> upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.<\/jats:p>","DOI":"10.1038\/s41598-020-72172-7","type":"journal-article","created":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T10:03:36Z","timestamp":1600855416000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension"],"prefix":"10.1038","volume":"10","author":[{"given":"Jiegen","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josepmaria","family":"Argemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Odena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Jiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Massey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Parrish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajanikanth","family":"Vadigepalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Altamirano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin","family":"Cabezas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pere","family":"Gines","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Caballeria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Snider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pau","family":"Sancho-Bru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizuo","family":"Akira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Bataller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,23]]},"reference":[{"key":"72172_CR1","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1002\/hep.29887","volume":"68","author":"JL Mellinger","year":"2018","unstructured":"Mellinger, J. 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