Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation
Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved..
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.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of hepatology - 63(2015), 3 vom: 10. Sept., Seite 670-8 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bárcena, Cristina [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.09.2016 Date Revised 13.11.2018 published: Print-Electronic CommentIn: J Hepatol. 2016 Apr;64(4):984-5. - PMID 26812076 Citation Status MEDLINE |
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| doi: |
10.1016/j.jhep.2015.04.013 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM248382608 |
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| 100 | 1 | |a Bárcena, Cristina |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation |
| 264 | 1 | |c 2015 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 08.09.2016 | ||
| 500 | |a Date Revised 13.11.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: J Hepatol. 2016 Apr;64(4):984-5. - PMID 26812076 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Chronic liver patients | |
| 650 | 4 | |a Experimental fibrosis | |
| 650 | 4 | |a Gas6/Axl serum levels | |
| 650 | 4 | |a HSC activation | |
| 650 | 4 | |a TAM receptors | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a NF-kappa B |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 650 | 7 | |a growth arrest-specific protein 6 |2 NLM | |
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| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Receptor Protein-Tyrosine Kinases |2 NLM | |
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| 650 | 7 | |a c-Mer Tyrosine Kinase |2 NLM | |
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| 700 | 1 | |a Stefanovic, Milica |e verfasserin |4 aut | |
| 700 | 1 | |a Tutusaus, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Joannas, Leonel |e verfasserin |4 aut | |
| 700 | 1 | |a Menéndez, Anghara |e verfasserin |4 aut | |
| 700 | 1 | |a García-Ruiz, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Sancho-Bru, Pau |e verfasserin |4 aut | |
| 700 | 1 | |a Marí, Montserrat |e verfasserin |4 aut | |
| 700 | 1 | |a Caballeria, Joan |e verfasserin |4 aut | |
| 700 | 1 | |a Rothlin, Carla V |e verfasserin |4 aut | |
| 700 | 1 | |a Fernández-Checa, José C |e verfasserin |4 aut | |
| 700 | 1 | |a de Frutos, Pablo García |e verfasserin |4 aut | |
| 700 | 1 | |a Morales, Albert |e verfasserin |4 aut | |
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