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Staging NAFLD: Diagnostic and Therapeutic Value of TAM Signaling
- Source :
- Cellular and Molecular Gastroenterology and Hepatology, Cellular and Molecular Gastroenterology and Hepatology, Vol 9, Iss 3, Pp 545-546 (2020)
- Publication Year :
- 2019
-
Abstract
- 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-/-, Mertk-/- and wild-type C57BL/6 mice were fed with Chow, High Fat Choline-Deficient Methionine-Restricted (HFD) or methionine-choline-deficient (MCD) diet. HSC activation, liver inflammation and cytokine/chemokine production were measured by qPCR, mRNA Array analysis, western blotting and ELISA. GAS6, soluble AXL (sAXL) and MERTK (sMERTK) levels were analyzed in control individuals, steatotic and NASH patients. 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-/- mice exhibited enhanced NASH, while Axl-/- mice were partially protected. In human serum, sAXL levels augmented even at initial stages, whereas GAS6 and sMERTK increased only in cirrhotic NASH patients. In agreement, sAXL increased in HFD-fed mice before fibrosis establishment, while bemcentinib prevented liver fibrosis/inflammation in early NASH. 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.<br />Graphical abstract
- Subjects :
- Oncology
Bemcentinib (BGB324)
ADAM17, a disintegrin and metalloproteinase 17
MPO, myeloperoxidase
GAS6/TAM Signaling
Non-alcoholic Fatty Liver Disease
Medicine
MMP9, matrix metalloproteinase-9
Original Research
TNF, tumor necrosis factor
NAS, NAFLD activity score
Gastroenterology
ELISA, enzyme-linked immunosorbent assay
MCP-1, monocyte chemoattractant protein-1
sMERTK, soluble MERTK
HSC, hepatic stellate cell
mRNA, messenger RNA
ECM, extracellular matrix
Disease Progression
Liver Fibrosis
LPS, lipopolysaccharide
NASH, nonalcoholic steatohepatitis
Signal Transduction
medicine.medical_specialty
sAXL, soluble AXL
MEDLINE
PBS, phosphate-buffered saline
TAM, Tyro3-Axl-Mertk
HFD, high-fat choline-deficient methionine-restricted diet
cDNA, complementary DNA
PA, palmitic acid
MCD, methionine-choline-deficient diet
Internal medicine
Hepatic Stellate Cells
Humans
KC, Kupffer cell
lcsh:RC799-869
KO, knockout
Hepatology
business.industry
Disease progression
nutritional and metabolic diseases
GAS6, Growth arrest-specific gene 6
WT, wild-type
IL, interleukin
ADAM10, a disintegrin and metalloproteinase 10
H&E, hematoxylin and eosin
lcsh:Diseases of the digestive system. Gastroenterology
NAFLD, nonalcoholic fatty liver disease
business
HCC, hepatocellular carcinoma
Value (mathematics)
PMH, primary mouse hepatocyte
Liver Inflammation
Subjects
Details
- ISSN :
- 2352345X
- Volume :
- 9
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cellular and molecular gastroenterology and hepatology
- Accession number :
- edsair.doi.dedup.....d4447636c8bfbf18ac86d901acecbc4e