Protective effects of Lipocalin-2 (LCN2) in acute and chronic liver injury indicate a novel function in liver homeostasis

Background and Aims: Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury models showed rapid and sustained LCN2 production, of which injured hepatocytes are the main source. The biological function of LCN2 however requires further elucidation. Methods: LCN2-/- mice were exposed to short- term application of CCl4, lipopolysaccharides and Concanavalin A and chronic experimental liver injury (long-term CCl4 or bile duct ligation). Subsequent injuries were assessed by liver function analysis, qRT-PCR for chemokine and cytokine expression, liver tissue Western blot, histology and TUNEL assay. Additionally, serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Results: Acute CCl4 intoxication showed increased liver damage in LCN2-/- mice indicated by significant higher levels of AST and ALT, plus increased expression of liver injury associated- and inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1/CCL2, resulting in activation of STAT1, STAT3 and JNK. LCN2-/- mice further showed a marked lipid droplet accumulation in hepatocytes demonstrated by oil red O staining and increased hepatocyte apoptosis. In the Concanavalin A model, LCN2-/- animals showed increased hepatocyte apoptosis. Similar findings were obtained after application of lipopolysaccharides and five days after bile duct ligation. In chronic models (bile duct ligation for 4 weeks or application of CCl4 for 8 weeks), LCN2-/- mice showed more severe fibrosis compared to controls. In addition, serum LCN2 levels found in diseased human livers were significantly higher than in control patients, but no difference was observed between cirrhotic and non-cirrhotic patients. Conclusion: Up-regulation of LCN2 not only is an indicator of liver damage but also suggests lipocalin to have a distinct endogenous hepato-protective effect on tissue homeostasis.