MOLMET
862
S2212-8778(19)30620-9
10.1016/j.molmet.2019.08.008
The Authors
Original Article
miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease
Pablo
Fernández-Tussy
1
13
pablo.fernandeztussy@yale.edu
David
Fernández-Ramos
1
13
dfernandez@cicbiogune.es
Fernando
Lopitz-Otsoa
1
flopitz@cicbiogune.es
Jorge
Simón
1
jsimon@cicbiogune.es
Lucía
Barbier-Torres
1
Lucia.BarbierTorres@cshs.org
Beatriz
Gomez-Santos
2
3
bgomezsantos@gmail.com
Maitane
Nuñez-Garcia
2
3
maitane.nunez@gmail.com
Mikel
Azkargorta
4
mazkargorta@cicbiogune.es
Virginia
Gutiérrez-de Juan
1
vgutierrez@cicbiogune.es
Marina
Serrano-Macia
1
mserrano@cicbiogune.es
Rubén
Rodríguez-Agudo
1
rrodriguez@cicbiogune.es
Paula
Iruzubieta
5
p.iruzubieta@gmail.com
Juan
Anguita
6
7
janguita@cicbiogune.es
Rui E.
Castro
8
ruieduardocastro@ff.ulisboa.pt
Devin
Champagne
9
Devin.Champagne@uvm.edu
Mercedes
Rincón
9
Mercedes.Rincon@med.uvm.edu
Felix
Elortza
4
felortza@cicbiogune.es
Anita
Arslanow
10
anita.arslanow@uks.eu
Marcin
Krawczyk
10
marcin.krawczyk@uks.eu
Frank
Lammert
10
frank.lammert@uks.eu
Mélanie
Kirchmeyer
11
kirchmeyer.melanie@gmail.com
Iris
Behrmann
11
iris.behrmann@uni.lu
Javier
Crespo
5
javiercrespo1991@gmail.com
Shelly C.
Lu
12
Shelly.Lu@cshs.org
José M.
Mato
1
director@cicbiogune.es
Marta
Varela-Rey
1
mvarela@cicbiogune.es
Patricia
Aspichueta
2
3
patricia.aspichueta@ehu.es
Teresa C.
Delgado
1
tcardoso@cicbiogune.es
María L.
Martínez-Chantar
1
∗
mlmartinez@cicbiogune.es
1
Liver disease Laboratory, Liver metabolism Laboratory, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160, Derio, Bizkaia, Spain
Liver disease Laboratory
Liver metabolism Laboratory
CIC bioGUNE
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Derio
Bizkaia
48160
Spain
Liver disease Laboratory, Liver metabolism Laboratory, CIC bioGUNE, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), 48160, Derio, Bizkaia, Spain
2
Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, 48940, Leioa, Bizkaia, Spain
Department of Physiology
Faculty of Medicine and Nursing
University of the Basque Country
Leioa
Bizkaia
48940
Spain
Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, 48940, Leioa, Bizkaia, Spain
3
Biocruces Health Research Institute, Barakaldo, Spain
Biocruces Health Research Institute
Barakaldo
Spain
Biocruces Health Research Institute, Barakaldo, Spain
4
Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, 48160, Spain
Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII
Bizkaia Science and Technology Park
Derio
48160
Spain
Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, 48160, Spain
5
Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, 39008, Spain
Department of Gastroenterology and Hepatology
Marqués de Valdecilla University Hospital
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Infection, Immunity and Digestive Pathology Group
Research Institute Marqués de Valdecilla (IDIVAL)
Santander
39008
Spain
Department of Gastroenterology and Hepatology, Marques de Valdecilla University Hospital, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd). Infection, Immunity and Digestive Pathology Group, Research Institute Marques de Valdecilla (IDIVAL), Santander, 39008, Spain
6
Macrophage and Tick Vaccine Laboratory, CIC bioGUNE, Bizkaia Science and Technology Park, Derio 48160 Bizkaia, Spain
Macrophage and Tick Vaccine Laboratory
CIC bioGUNE, Bizkaia Science and Technology Park
Derio 48160 Bizkaia
Spain
Macrophage and Tick Vaccine Laboratory, CIC bioGUNE, Bizkaia Science and Technology Park, Derio 48160 Bizkaia, Spain
7
Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain
Ikerbasque, Basque Foundation for Science
Bilbao
48013
Spain
Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain
8
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
Research Institute for Medicines (iMed.ULisboa)
Faculty of Pharmacy
Universidade de Lisboa
Lisbon
Portugal
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
9
Department of Medicine, University of Vermont College of Medicine, Burlington, 05405, VT, USA
Department of Medicine
University of Vermont College of Medicine
Burlington
VT
05405
USA
Department of Medicine, University of Vermont College of Medicine, Burlington, 05405, VT, USA
10
Department of Medicine II, Saarland University Medical Center, 66421, Homburg, Germany
Department of Medicine II
Saarland University Medical Center
Homburg
66421
Germany
Department of Medicine II, Saarland University Medical Center, 66421, Homburg, Germany
11
Signal Transduction Laboratory, Life Sciences Research Unit, University of Luxembourg, House of Biomedicine II, 4367, Belvaux, Luxembourg
Signal Transduction Laboratory
Life Sciences Research Unit
University of Luxembourg
House of Biomedicine II
Belvaux
4367
Luxembourg
Signal Transduction Laboratory, Life Sciences Research Unit, University of Luxembourg, House of Biomedicine II, 4367, Belvaux, Luxembourg
12
Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Division of Digestive and Liver Diseases
Cedars-Sinai Medical Center
Los Angeles
CA
USA
Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA
∗
Corresponding author. CIC bioGUNE, Ed. 801A Parque Tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain. Fax: +34 944 061301.
CIC bioGUNE
Ed. 801A Parque Tecnológico de Bizkaia
Derio
Bizkaia
48160
Spain
13
Pablo Fernández-Tussy and David Fernández-Ramos are Joint first authors.
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.
Graphical abstract
Image 1
Highlights
•
The microRNA miR-873-5p is upregulated in human and murine NAFLD/NASH livers.
•
miR-873-5p upregulation downregulates GNMT in the liver.
•
miR-873-5p inhibition reduces liver steatosis, inflammation and fibrosis in in vivo NAFLD mouse models.
•
GNMT is a hepatic metabolic hub with mitochondria activity through the regulation of Complex II of the ETC.
•
Mitochondrial GNMT deficiency compromises ETC functionality and metabolism.
Keywords
NASH
GNMT
Mitochondria
β-oxidation
Metabolism
microRNA
KBJ00000000011542
2019-10-26T18:47:15
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S2212-8778(19)30620-9
10.1016/j.molmet.2019.08.008
MOLMET
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862
FLA
NON-CRC
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2019-08-16T05:22:01Z
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