Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Autor: Zheng K; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), Madrid, Spain.; Department of Anesthesiology, Nanjing Pukou District Hospital of Chinese Medicine Central Laboratory affiliated to Nanjing University of Chinese Medicine, Nanjing, China., Hao F; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), Madrid, Spain.; Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China., Medrano-Garcia S; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), Madrid, Spain., Chen C; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; Department of General Surgery, Wuxi Xishan People's Hospital, Wuxi, China.; Department of General Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China., Guo F; Department of Obstetrics and Gynaecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China., Morán-Blanco L; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain., Rodríguez-Perales S; Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain., Torres-Ruiz R; Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain., Peligros MI; Servicio de Anatomía Patológica Hospital General Universitario Gregorio Marañón, Madrid, Spain., Vaquero J; Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain., Bañares R; Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain., Gómez Del Moral M; 12 de Octubre Health Research Institute (imas12), Madrid, Spain.; Department of Cell Biology, Complutense University School of Medicine, Madrid, Spain., Regueiro JR; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), Madrid, Spain., Martínez-Naves E; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), Madrid, Spain., Mohamed MR; Department of Clinical Medicine III, University Hospital Aachen, UKA, Aachen, Germany., Gallego-Durán R; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Sevilla, Spain., Maya D; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Sevilla, Spain., Ampuero J; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Sevilla, Spain., Romero-Gómez M; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Sevilla, Spain., Gilbert-Ramos A; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, Spain., Guixé-Muntet S; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, Spain., Fernández-Iglesias A; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, Spain., Gracia-Sancho J; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona, Spain.; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Coll M; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Laboratorio de Plasticidad de Células Hepáticas y Reparación de Tejidos, Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain., Graupera I; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Laboratorio de Plasticidad de Células Hepáticas y Reparación de Tejidos, Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Liver Unit, Hospital Clinic, Barcelona, Spain., Ginès P; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.; Liver Unit, Hospital Clinic, Barcelona, Spain., Ciudin A; Endocrinology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, Spain., Rivera-Esteban J; Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, Spain., Pericàs JM; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Liver Unit, Internal Medicine Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Barcelona, Spain., Frutos MD; Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain., Ramos Molina B; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Laboratorio de Obesidad y Metabolismo, Instituto de Investigación Biomédica de Murcia (IMIB-Arrixaca), Murcia, Spain., Herranz JM; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Hepatology Programme, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain., Ávila MA; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Hepatology Programme, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain., Nevzorova YA; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain., Fernández-Malavé E; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), Madrid, Spain., Cubero FJ; Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, Madrid, Spain. fcubero@ucm.es.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain. fcubero@ucm.es.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. fcubero@ucm.es.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2023 Aug 10; Vol. 14 (8), pp. 514. Date of Electronic Publication: 2023 Aug 10.
DOI: 10.1038/s41419-023-06029-y
Abstrakt: Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS -/- ) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl 4 ) intoxication and bile duct ligation (BDL). In wild-type (N-RAS +/+ ) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS +/+ counterparts, N-RAS -/- mice subjected to either CCl 4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl 4 or BDL, N-RAS -/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
(© 2023. The Author(s).)
Databáze: MEDLINE
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