biostudies-literatureChen JConsejo Nacional de Ciencia y TecnologíaNational Institute on Alcohol Abuse and AlcoholismInstituto de Salud Carlos IIINIDDK NIH HHSNIEHS NIH HHSNIAAA NIH HHSNCI NIH HHSInstitució Catalana de Recerca i Estudis AvançatsEuropean Regional Development Fund15558https://www.ebi.ac.uk/biostudies/studies/S-EPMC7512007biostudies-literatureUnknown10(1)Advanced fibrosis and portal hypertension influence short-term mortality. 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 LCN2 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. Lcn2^-/- mice were protected from liver fibrosis caused by either ethanol or CCl₄ exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2^-/- mice exposed to CCl₄, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.Scientific reportsHepatic lipocalin 2 promotes liver fibrosis and portal hypertension.PMC7512007PI16/00043R01 AA018873PI17/00673F31 AA024969P30 CA016086U01 AA021908R01 AA0162581U01AA021908-01U01 AA020821P30 ES010126R01 DK110355T32 AA007463Gao BAltamirano JChen JBataller RMassey VSancho-Bru PCabezas JAkira SArgemi JXu MJParrish AGines PCaballeria JVadigepalli ROdena GCai YSnider NRusyn IfalseHepatic lipocalin 2 promotes liver fibrosis and portal hypertension.Advanced fibrosis and portal hypertension influence short-term mortality. 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 LCN2 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. Lcn2^-/- mice were protected from liver fibrosis caused by either ethanol or CCl₄ exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2^-/- mice exposed to CCl₄, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.2020-01-01T00:00:00Z2020 Sep2024-12-03T19:05:53.902Z2020-10-08T07:13:08ZS-EPMC75120073296811010.1038/s41598-020-72172-7