lipocalin-2在肝再生中的作用

O R I G I N A L A R T I C L E

The role of lipocalin-2in liver regeneration

Katrin Kienzl-Wagner 1*,Alexander R.Moschen 2,3*,Sabine Geiger 2,3,Alexandra Bichler 3,Felix Aigner 1,Gerald Brandacher 4,Johann Pratschke 1and Herbert Tilg 2,3

1Department of Visceral,Transplant and Thoracic Surgery,Center of Operative Medicine,Innsbruck Medical University,Innsbruck,Austria 2Christian Doppler Research Laboratory for Gut Inflammation,Innsbruck Medical University,Innsbruck,Austria

3Department of Internal Medicine I (Gastroenterology,Endocrinology &Metabolism),Innsbruck Medical University,Innsbruck,Austria 4

Department of Plastic and Reconstructive Surgery,Johns Hopkins University School of Medicine,Baltimore,MD,USA

Keywords

biomarker –hepatic proliferation –LCN2–lipocalin-2–liver regeneration –partial hepatectomy

Correspondence

Herbert Tilg,MD,Department of Internal Medicine I,Innsbruck Medical University,Anichstrasse 35,Innsbruck 6020,Austria Tel:+4351250423540Fax:+4351250423538

e-mail:herbert.tilg@i-med.ac.at Received 13November 2013Accepted 1July 2014DOI:10.1111/liv.12634

Abstract

Background &Aims:Various immune mediators such as interleukin-6(IL-6)have been implicated in the process of liver regeneration.Lipocalin-2(LCN2)has been recently characterized as a prototypic immune mediator produced by various cell types being involved mainly in host defence.In addition,numerous studies have demonstrated its clinical value as a biomar-ker.This study aimed at defining the role of LCN2in liver regenera-tion.Methods:We studied LCN2expression in wild-type mice in a model of partial hepatectomy (PH).Furthermore,we evaluated liver regeneration after PH in LCN-deficient mice compared to littermate controls.Serum levels of LCN2were assessed in a small group of patients undergoing hepatic resec-tion.Results:LCN2is dramatically induced in livers and sera of wild-type mice after PH,whereas liver LCN2-receptor expression was decreased.Sham operations did not affect hepatic and serum LCN2expression.Although LCN2-deficient mice exhibited increased baseline liver expression indices,LCN2-deficient mice did not differ from wild-type mice with respect to hepatic proliferation suggesting that this molecule is not involved in hepatic repair.Only serum IL-1b levels were slightly lower in LCN À/Àmice,whereas IL-6serum levels did not differ between various tested animal groups.In humans undergoing hepatic resection,LCN2levels increased significantly within 24h following surgery.Conclusions:LCN2,although massively induced in mice after PH,is not relevant in murine hepatic regeneration.Further,human studies have to define whether LCN2could evolve as biomarker after liver surgery.

The liver has the unique ability to fully regenerate after major tissue loss induced by viruses,toxins,autoim-mune disease,resection of primary or metastatic tumours as well as in the context of partial liver trans-plantation (1).Enhancing the regenerative capacity of the liver is crucial for the development of specific thera-pies for chronic liver disease and expanding indications for liver resection.Even though the last years have seen remarkable progress in characterizing the molecular and cellular mechanisms of liver regeneration,the multiple components and complex networks that orchestrate the regeneration process remain to be further elucidated.The current understanding of liver regeneration encompasses various cytokines,growth factors and met-abolic networks that link liver function with cell growth and proliferation.In normal liver regeneration as seen

after partial hepatectomy (PH),the liver mass is replen-ished by replication of existing hepatocytes without involvement of stem or progenitor cells (2).Upon liver resection,expression of TNF-a and IL-6is induced in Kupffer cells by various mechanisms including lipopoly-saccharide resulting in activation of STAT3in hepato-cytes and subsequent entry into the cell cycle.Key mitogenic factors that drive cell cycle progression are hepatocyte growth factor,epidermal growth factor and vascular endothelial growth factor.Termination of hepatocyte proliferation is controlled by the action of transforming growth factor b and activins (1,3–5).

Mounting evidence suggests that lipocalin-2(LCN2)is an important modulator of proliferative and regenera-tive processes.LCN2is a 25kDa glycoprotein of a b -barrel shaped structure with the ability to bind small hydrophobic ligands and to form complexes with soluble macromolecules (6).LCN2so far has been ascribed great functional diversity.It has been shown to

*Both authors contributed equally to this study.Liver International (2014)

©2014John Wiley &Sons A/S.Published by John Wiley &Sons Ltd

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Liver International ISSN

1478-3223