Hepatocyte autotaxin expression promotes liver fibrosis and ... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Kaffe, Eleanna1; Katsifa, Aggeliki1; Xylourgidis, Nikos1; Ninou, Ioanna1; Zannikou, Markella1; Harokopos, Vaggelis1; Foka, Pelagia2; Dimitriadis, Alexios2; Evangelou, Kostas3; Moulas, Anargyros N.4; Georgopoulou, Urania2; Gorgoulis, Vassilis G.3,5,6; Dalekos, George N.7; Aidinis, Vassilis*,1

1Division of ImmunologyBiomedical Sciences Research Center Alexander FlemingAthensGreece

2Laboratory of Molecular VirologyHellenic Pasteur InstituteAthensGreece

3Department of Histology and EmbryologySchool of Medicine, University of AthensAthensGreece

4Laboratory of BiochemistryTechnological Educational Institute of ThessalyLarissaGreece

5Biomedical Research FoundationAcademy of AthensAthensGreece

6Institute for Cancer SciencesUniversity of Manchester, Manchester Academic Health Science CentreManchesterUK

7Department of Medicine and Research Laboratory of Internal MedicineMedical School, University of ThessalyLarissaGreece

* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Vassilis Aidinis, Ph.D.
Division of Immunology, Biomedical Sciences Research Center Alexander Fleming
34 Fleming Street
16672 Athens, Greece
E‐mail: [email protected]
Tel: +302109654382

Abstract

Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth‐factor–like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however, little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver disease (CLD) patients of different etiologies, associated with shorter overall survival. In mice, different hepatotoxic stimuli linked with the development of different forms of CLDs were shown to stimulate hepatocyte ATX expression, leading to increased LPA levels, activation of hepatic stellate cells (HSCs), and amplification of profibrotic signals. Hepatocyte‐specific, conditional genetic deletion and/or transgenic overexpression of ATX established a liver profibrotic role for ATX/LPA, whereas pharmacological ATX inhibition studies suggested ATX as a possible therapeutic target in CLDs. In addition, hepatocyte ATX ablation and the consequent deregulation of lipid homeostasis was also shown to attenuate hepatocellular carcinoma (HCC) development, thus implicating ATX/LPA in the causative link of cirrhosis and HCC. Conclusion: ATX is a novel player in the pathogenesis of liver fibrosis and cancer and a promising therapeutic target. (Hepatology 2017;65:1369‐1383).