Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
Sci Rep. 2020 Sep 23;10(1):15558. doi: 10.1038/s41598-020-72172-7.
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 CCl exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2 mice exposed to CCl, 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.
肝纤维化和门静脉高压会影响短期死亡率。脂钙素 2（LCN2）调节感染反应，并在肝损伤时增加。我们探索了肝内 LCN2 在伴有肝纤维化和门静脉高压的人类酒精性肝炎（AH）中的作用，以及在实验性小鼠纤维化中的作用。我们发现，肝 LCN2 表达和血清 LCN2 水平显著增加，并与 AH 患者的疾病严重程度和门静脉高压相关。在对照人类肝脏中，LCN2 仅在单核细胞中表达，而在 AH 肝脏中其表达显著诱导，不仅在单核细胞中，而且在肝细胞中也显著诱导。Lcn2 小鼠可免受乙醇或 CCl 暴露引起的肝纤维化。微阵列分析显示，暴露于 CCl 的 Lcn2 小鼠中基质体、细胞周期和免疫相关基因集下调，同时 Timp1 和 Edn1 表达减少。AH 患者的肝 COL1A1、TIMP1 和关键 EDN1 系统成分表达升高，并与肝 LCN2 表达相关。在体外，重组 LCN2 诱导 COL1A1 表达。LCN2 的过表达增加了 HIF1A，从而介导了 EDN1 的上调。LCN2 有助于 AH 中的肝纤维化和门静脉高压，可能代表一个新的治疗靶点。
