A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target.
Adult
Aged
Animals
Benzocycloheptenes
/ pharmacology
Biomarkers
/ blood
Biopsy
Cells, Cultured
Disease Models, Animal
Disease Progression
Female
Hepatic Stellate Cells
/ drug effects
Hepatocytes
/ drug effects
Humans
Intercellular Signaling Peptides and Proteins
/ genetics
Kupffer Cells
/ drug effects
Liver
/ cytology
Liver Cirrhosis
/ immunology
Male
Mice
Mice, Knockout
Middle Aged
Non-alcoholic Fatty Liver Disease
/ blood
Primary Cell Culture
Proto-Oncogene Proteins
/ antagonists & inhibitors
Proto-Oncogene Proteins c-akt
/ metabolism
Receptor Protein-Tyrosine Kinases
/ antagonists & inhibitors
STAT3 Transcription Factor
/ metabolism
Signal Transduction
/ drug effects
Triazoles
/ pharmacology
c-Mer Tyrosine Kinase
/ genetics
Axl Receptor Tyrosine Kinase
Bemcentinib (BGB324)
GAS6/TAM Signaling
Hepatic Stellate Cells
Liver Fibrosis
Liver Inflammation
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2020
2020
Historique:
received:
26
04
2019
revised:
25
10
2019
accepted:
28
10
2019
pubmed:
7
11
2019
medline:
4
5
2021
entrez:
6
11
2019
Statut:
ppublish
Résumé
GAS6 signaling, through the TAM receptor tyrosine kinases AXL and MERTK, participates in chronic liver pathologies. Here, we addressed GAS6/TAM involvement in Non-Alcoholic SteatoHepatitis (NASH) development. GAS6/TAM signaling was analyzed in cultured primary hepatocytes, hepatic stellate cells (HSC) and Kupffer cells (KCs). Axl In primary mouse cultures, GAS6 or MERTK activation protected primary hepatocytes against lipid toxicity via AKT/STAT-3 signaling, while bemcentinib (small molecule AXL inhibitor BGB324) blocked AXL-induced fibrogenesis in primary HSCs and cytokine production in LPS-treated KCs. Accordingly; bemcentinib diminished liver inflammation and fibrosis in MCD- and HFD-fed mice. Upregulation of AXL and ADAM10/ADAM17 metalloproteinases increased sAXL in HFD-fed mice. Transcriptome profiling revealed major reduction in fibrotic- and inflammatory-related genes in HFD-fed mice after bemcentinib administration. HFD-fed Mertk AXL signaling, increased in NASH patients, promotes fibrosis in HSCs and inflammation in KCs, while GAS6 protects cultured hepatocytes against lipotoxicity via MERTK. Bemcentinib, by blocking AXL signaling and increasing GAS6 levels, reduces experimental NASH, revealing AXL as an effective therapeutic target for clinical practice.
Sections du résumé
BACKGROUND AND AIMS
GAS6 signaling, through the TAM receptor tyrosine kinases AXL and MERTK, participates in chronic liver pathologies. Here, we addressed GAS6/TAM involvement in Non-Alcoholic SteatoHepatitis (NASH) development.
METHODS
GAS6/TAM signaling was analyzed in cultured primary hepatocytes, hepatic stellate cells (HSC) and Kupffer cells (KCs). Axl
RESULTS
In primary mouse cultures, GAS6 or MERTK activation protected primary hepatocytes against lipid toxicity via AKT/STAT-3 signaling, while bemcentinib (small molecule AXL inhibitor BGB324) blocked AXL-induced fibrogenesis in primary HSCs and cytokine production in LPS-treated KCs. Accordingly; bemcentinib diminished liver inflammation and fibrosis in MCD- and HFD-fed mice. Upregulation of AXL and ADAM10/ADAM17 metalloproteinases increased sAXL in HFD-fed mice. Transcriptome profiling revealed major reduction in fibrotic- and inflammatory-related genes in HFD-fed mice after bemcentinib administration. HFD-fed Mertk
CONCLUSION
AXL signaling, increased in NASH patients, promotes fibrosis in HSCs and inflammation in KCs, while GAS6 protects cultured hepatocytes against lipotoxicity via MERTK. Bemcentinib, by blocking AXL signaling and increasing GAS6 levels, reduces experimental NASH, revealing AXL as an effective therapeutic target for clinical practice.
Identifiants
pubmed: 31689560
pii: S2352-345X(19)30146-8
doi: 10.1016/j.jcmgh.2019.10.010
pmc: PMC7013198
pii:
doi:
Substances chimiques
Benzocycloheptenes
0
Biomarkers
0
Intercellular Signaling Peptides and Proteins
0
Proto-Oncogene Proteins
0
STAT3 Transcription Factor
0
Stat3 protein, mouse
0
Triazoles
0
growth arrest-specific protein 6
0
bemcentinib
0ICW2LX8AS
Mertk protein, mouse
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
c-Mer Tyrosine Kinase
EC 2.7.10.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Axl Receptor Tyrosine Kinase
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
349-368Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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