title: Protective effects of lipocalin-2 (LCN2) in acute liver injury suggest a novel function in liver homeostasis.
abstract: Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury induces rapid and sustained LCN2 production by injured hepatocytes. However, the precise biological function of LCN2 in liver is still unknown. In this study, LCN2(-/-) mice were exposed to short term application of CCl4, lipopolysaccharide and Concanavalin A, or subjected to 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. Serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Acute CCl4 intoxication showed increased liver damage in LCN2(-/-) mice indicated by higher levels of aminotransferases, and increased expression of inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1/CCL2, resulting in sustained activation of STAT1, STAT3 and JNK pathways. Hepatocytes of LCN2(-/-) mice showed lipid droplet accumulation and increased apoptosis. Hepatocyte apoptosis was confirmed in the Concanavalin A and lipopolysaccharide models. In chronic models (4weeks bile duct ligation or 8weeks CCl4 application), LCN2(-/-) mice showed slightly increased fibrosis compared to controls. Interestingly, serum LCN2 levels in diseased human livers were significantly higher compared to controls, but no differences were observed between cirrhotic and non-cirrhotic patients. Upregulation of LCN2 is a reliable indicator of liver damage and has significant hepato-protective effect in acute liver injury. LCN2 levels provide no correlation to the degree of liver fibrosis but show significant positive correlation to inflammation instead.
authors: Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University Hospital, Germany. ekamphorst@ukaachen.de
authors: Erawan
authors: E
authors: Borkham-Kamphorst
authors: Eddy
authors: E
authors: van de Leur
authors: Henning W
authors: HW
authors: Zimmermann
authors: Karlin Raja
authors: KR
authors: Karlmark
authors: Lidia
authors: L
authors: Tihaa
authors: Ute
authors: U
authors: Haas
authors: Frank
authors: F
authors: Tacke
authors: Thorsten
authors: T
authors: Berger
authors: Tak W
authors: TW
authors: Mak
authors: Ralf
authors: R
authors: Weiskirchen
mesh_terms: D000208:Acute Disease; D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000601:surgery; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D008026:Ligation / Q000009:adverse effects; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000209:Acute-Phase Proteins; D018925:Chemokines; D016207:Cytokines; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D003208:Concanavalin A; C071332:Lcn2 protein, mouse; D002251:Carbon Tetrachloride