Reference : miR-873-5p targets mitochondrialGNMT-Complex II interface contributing tonon-alcoholi...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/42583
miR-873-5p targets mitochondrialGNMT-Complex II interface contributing tonon-alcoholic fatty liver disease
English
Fernández-Tussy, Pablo mailto [CIC bioGUNE > Liver disease Laboratory]
Fernández-Ramos, David mailto [CIC bioGUNE > Liver metabolism Laboratory]
Lopitz-Otsoa, Fernando mailto [CIC bioGUNE > Liver metabolism Laboratory]
Simón, Jorge mailto [CIC bioGUNE > Liver disease Laboratory]
Barbier-Torres, Lucía mailto [CIC bioGUNE > Liver disease Laboratory]
Gomez-Santos, Beatriz mailto [Universidad del País Vasco (España) = University of the Basque Country (Spain) - UPV > Department of Physiology, Faculty of Medicine and Nursing]
Nuñez-Garcia, Maitane mailto [Universidad del País Vasco (España) = University of the Basque Country (Spain) - UPV > Department of Physiology, Faculty of Medicine and Nursing]
Azkargorta, Mikel mailto [CICbioGUNE, CIBERehd > 2Proteomics Platform]
Gutiérrez-de Juan, Virginia mailto [CIC bioGUNE > Metabolomics]
Serrano-Macia, Marina mailto [CIC bioGUNE > Liver disease Laboratory]
Rodríguez-Agudo, Rubén mailto [CIC bioGUNE > Liver disease Laboratory]
Iruzubieta, Paula mailto [Marques de Valdecilla University Hospital > Gastroenterology and Hepatology Service]
Anguita, Juan mailto [Ikerbasque, Basque Foundation for Science > Macrophage and Tick Vaccine Laboratory, CIC bioGUNE]
Castro, Rui Eduardo mailto [Universidade de Lisboa > Faculty of Pharmacy]
Champagne, Devin mailto [University of Vermont College of Medicine > Department of Medicine]
Rincón, Mercedes mailto [University of Vermont, College of Medicine > Department of Medicine]
Elortza, Felix mailto [CIC bioGUNE > Proteomics Platform]
Arslanow, Anita mailto [Saarland University Medical Center > Department of Medicine II]
Krawczyk, Marcin mailto [Saarland University Medical Center > Department of Medicine II]
Lammert, Frank mailto [Saarland University Medical Center > Department of Decine II]
Kirchmeyer, Mélanie mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Crespo, Javier mailto [University Hospital Marques de Valdecilla > Gastroenterology and Hepatology Service]
Lu, Shelly mailto [Cedars-Sinai Medical Center, Los Angeles, CA, USA > Division of Digestive and Liver Diseases]
Mato, José mailto [CIC bioGUNE > Liver Metabolism]
Varela-Rey, Marta mailto [CIC bioGUNE > Liver disease]
Aspichueta, Patricia mailto [Universidad del País Vasco (España) = University of the Basque Country (Spain) - UPV > Faculty of Medicine and Dentistry]
Cardoso Delgado, Teresa mailto [CIC bioGUNE > Liver disease]
Martinez_Chantar, Maria mailto [Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) > Liver disease Laboratory, Liver metabolism Laboratory, CIC bioGUNE]
16-Aug-2019
Molecular Metabolism
Yes
International
[en] microRNA ; Metabolism ; Mitochondria
[en] Objective:Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolicpathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation andfibrosis.The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, isdownregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression.Methods:miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Differentin vitroandin vivoNAFLD murinemodels were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy.Results:We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria.In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinicalmurine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating withhepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation andfibrosis byenhancing fatty acidb-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment.Conclusion:GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activityin the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment.
http://hdl.handle.net/10993/42583

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