miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease
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Date
2019-08-16Author
Fernández Tussy, Pablo
Fernández Ramos, David
Lopitz Otsoa, Fernando
Simon, Jorge
Barbier Torres, Lucía
Gómez Santos, Beatriz
Nuñez García, Maitane
Azkargorta, Mikel
Serrano Maciá, Marina
Gutiérrez de Juan, Virginia
Serrano Maciá, Marina
Rodríguez Agudo, Rubén
Iruzubieta, Paula
Anguita Castillo, Juan de Dios
Castro, Rui E.
Champagne, Devin
Rincon, Mercedes
Elortza, Felix
Arslanow, Anita
Krawczyk, Marcin
Lammert, Frank
Kirchmeyer, Melanie
Behrmann, Iris
Crespo, Javier
Lu, Shelly C.
Mato, José M.
Varela Rey, Marta
Aspichueta Celaá, Patricia
Delgado, Teresa C.
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Molecular Metabolism 29 : 40-54 (2019)
Abstract
Objective: Non-alcoholic fatly liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated 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. Different in vitro and in vivo NAFLD murine models 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 mitochondria! functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid beta-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 mitochondria! functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment. (C) 2019 The Authors. Published by Elsevier GmbH.
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Except where otherwise noted, this item's license is described as © 2019 The Authors. Published by Elsevier GmbH. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.