A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target
| العنوان: | A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target |
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| المؤلفون: | Montserrat Marí, Anna Tutusaus, Cristina Aresté, Estefanía de Gregorio, Mar Coll, Albert Morales, James B. Lorens, Pablo García de Frutos, Gro Gausdal, Anna Colell, Blanca Cucarull, Isabel Graupera, Helena Cristóbal |
| المساهمون: | Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Fundació La Marató de TV3, Generalitat de Catalunya |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology (CMGH) Cellular and Molecular Gastroenterology and Hepatology, Vol 9, Iss 3, Pp 349-368 (2020) |
| بيانات النشر: | Elsevier, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Liver Cirrhosis, Male, medicine.medical_treatment, Biopsy, Bemcentinib (BGB324), GAS6/TAM Signaling, Mice, 0302 clinical medicine, Fibrosis, Non-alcoholic Fatty Liver Disease, Medicine, Cells, Cultured, Mice, Knockout, Gastroenterology, Middle Aged, Benzocycloheptenes, Cytokine, Editorial, Lipotoxicity, Liver, Disease Progression, Intercellular Signaling Peptides and Proteins, Liver Fibrosis, 030211 gastroenterology & hepatology, Female, Signal Transduction, Adult, STAT3 Transcription Factor, AXL Inhibitor BGB324, Kupffer Cells, Primary Cell Culture, 03 medical and health sciences, Proto-Oncogene Proteins, Hepatic Stellate Cells, Animals, Humans, lcsh:RC799-869, Aged, Hepatology, c-Mer Tyrosine Kinase, business.industry, GAS6, Receptor Protein-Tyrosine Kinases, nutritional and metabolic diseases, MERTK, Triazoles, medicine.disease, Axl Receptor Tyrosine Kinase, Disease Models, Animal, 030104 developmental biology, Cancer research, Hepatic stellate cell, Hepatocytes, lcsh:Diseases of the digestive system. Gastroenterology, Steatohepatitis, business, Proto-Oncogene Proteins c-akt, Biomarkers, Liver Inflammation |
| الوصف: | 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. This study was funded by grants from Instituto de Salud Carlos III (PI16/00930 and PI19/01410 to Montserrat Marí) and CIBEREHD; Ministerio de Economía y Competitividad (SAF2015-66515-R and RTI2018-095672-B-I00 to Albert Morales and Pablo García de Frutos, and RTI2018-095572-B-100 to Anna Colell), and co-funded by FEDER (Fondo Europeo de Desarrollo Regional, Unión Europea), Fundació Marató de TV3 (to Pablo García de Frutos), AGAUR (2017_SGR_177 to Albert Morales), and CERCA Programme/ Generalitat de Catalunya |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::abd0af491353a59385b69d42035b9ec9 http://hdl.handle.net/10261/223520 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....abd0af491353a59385b69d42035b9ec9 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |