Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

• DOI: 10.1016/j.jhep.2015.04.013
• Publication Date: 2015-04-21T02:29:30Z
• Authors: 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...; Pablo García de F...; Albert Morales
• Keywords: Hepatic stellate cell; GAS6; Hepatic fibrosis; Chronic liver disease

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, receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response carcinogenesis.MethodsHSCs were obtained WT Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the inhibitor BGB324, analyzed western blot real-time PCR. Experimental fibrosis was studied CCl4-treated combination inhibitor. serum levels measured alcoholic disease (ALD) hepatitis C virus (HCV) patients.ResultsIn primary mouse HSCs, paralleled HSC activation. rGas6 phosphorylated AKT prior phenotypic changes, while siRNA silencing reduced Moreover, BGB324 blocked Axl/AKT phosphorylation diminished In addition, mice displayed decreased activation vitro fibrogenesis after damage CCl4 administration. Similarly, collagen deposition CCl4-induced mice. Importantly, increased ALD HCV patients, inversely correlating functionality.ConclusionsThe Gas6/Axl axis required full increase parallel progression. targeting may be therapeutic strategy management.