• Cristina Bárcena, Milica Stefanovic, Anna Tutusaus, Leonel Joannas, Anghara Menéndez, Carmen García-Ruiz, Pau Sancho-Bru, Montserrat Marí, Joan Caballeria, Carla V Rothlin, José C Fernández-Checa, de Frutos Pablo García PG Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Catalonia, Spain. Electronic address: pablo.garcia@iibb.csic.es., and Albert Morales.
• Liver Unit, Hospital Clinic, IDIBAPS-CIBEK, CIBEREHD, Barcelona, Catalonia, Spain; Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Catalonia, Spain.
• J. Hepatol. 2015 Sep 1; 63 (3): 670-8.

Background & AimsLiver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis.MethodsHSCs were obtained from WT and Axl(-/-) mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated WT and Axl(-/-) mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients.ResultsIn primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl(-/-) mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality.ConclusionsThe Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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