Elsevier

Journal of Hepatology

Volume 63, Issue 3, September 2015, Pages 670-678
Journal of Hepatology

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

https://doi.org/10.1016/j.jhep.2015.04.013Get rights and content
Under a Creative Commons license
open access

Background & Aims

Liver 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.

Methods

HSCs 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.

Results

In 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.

Conclusions

The 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.

Abbreviations

ALD
alcoholic liver disease
COL1A1
Collagen 1A1
ECM
extracellular matrix
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HSCs
hepatic stellate cells
MMP
matrix metalloproteinase
PCNA
proliferating cell nuclear antigen
ProS
Protein S
rGas6
recombinant Gas6
sAxl
soluble Axl
α-SMA
α-smooth muscle actin
TAM receptor
Tyro3/Axl/MERTK receptor
TGF-β1
transforming growth factor-β1
WT
wild type

Keywords

Experimental fibrosis
TAM receptors
HSC activation
Chronic liver patients
Gas6/Axl serum levels

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