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miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease.

  • Author(s): Fernández-Tussy, Pablo;
  • Fernández-Ramos, David;
  • Lopitz-Otsoa, Fernando;
  • Simón, Jorge;
  • Barbier-Torres, Lucía;
  • Gomez-Santos, Beatriz;
  • Nuñez-Garcia, Maitane;
  • Azkargorta, Mikel;
  • Gutiérrez-de Juan, Virginia;
  • Serrano-Macia, Marina;
  • Rodríguez-Agudo, Rubén;
  • Iruzubieta, Paula;
  • Anguita, Juan;
  • Castro, Rui E;
  • Champagne, Devin;
  • Rincón, Mercedes;
  • Elortza, Felix;
  • Arslanow, Anita;
  • Krawczyk, Marcin;
  • Lammert, Frank;
  • Kirchmeyer, Mélanie;
  • Behrmann, Iris;
  • Crespo, Javier;
  • Lu, Shelly C;
  • Mato, José M;
  • Varela-Rey, Marta;
  • Aspichueta, Patricia;
  • Delgado, Teresa C;
  • Martínez-Chantar, María L
  • et al.
Abstract

OBJECTIVE:Non-alcoholic fatty 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 mitochondrial 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 β-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 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.

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