miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease.
Adult
Animals
Antagomirs
/ metabolism
Disease Models, Animal
Electron Transport Complex II
/ genetics
Female
Glycine N-Methyltransferase
/ deficiency
Hepatocytes
/ cytology
Humans
Lipid Peroxidation
Liver
/ metabolism
Male
Mice
Mice, Inbred C57BL
MicroRNAs
/ antagonists & inhibitors
Middle Aged
Mitochondria
/ metabolism
Non-alcoholic Fatty Liver Disease
/ drug therapy
Up-Regulation
GNMT
Metabolism
Mitochondria
NASH
microRNA
β-oxidation
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
25
06
2019
revised:
06
08
2019
accepted:
12
08
2019
entrez:
1
11
2019
pubmed:
2
11
2019
medline:
27
5
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 31668391
pii: S2212-8778(19)30620-9
doi: 10.1016/j.molmet.2019.08.008
pmc: PMC6728756
pii:
doi:
Substances chimiques
Antagomirs
0
MIRN873 microRNA, human
0
MicroRNAs
0
Electron Transport Complex II
EC 1.3.5.1
Glycine N-Methyltransferase
EC 2.1.1.20
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
40-54Subventions
Organisme : NIDDK NIH HHS
ID : R41 DK112429
Pays : United States
Organisme : NIDDK NIH HHS
ID : R41 DK117760
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.
Références
Nature. 2010 Mar 4;464(7285):121-5
pubmed: 20203611
Hepatology. 2016 Jul;64(1):73-84
pubmed: 26707365
Hepatology. 2015 Oct;62(4):1237-48
pubmed: 26109312
Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11-20
pubmed: 28930295
Hepatology. 2013 Oct;58(4):1497-507
pubmed: 23299992
J Proteomics. 2012 Dec 21;77:167-75
pubmed: 22960565
Hepatology. 2013 Oct;58(4):1296-305
pubmed: 23505042
J Biol Chem. 2014 Oct 17;289(42):28971-86
pubmed: 25183005
Hepatology. 2010 Jun;51(6):1972-8
pubmed: 20209604
Lab Invest. 2015 Feb;95(2):223-36
pubmed: 25531568
Hepatology. 2006 Sep;44(3):581-91
pubmed: 16941682
Dis Model Mech. 2014 Nov;7(11):1287-96
pubmed: 25261569
Oncotarget. 2015 Feb 10;6(4):2509-23
pubmed: 25650664
J Biol Chem. 1957 May;226(1):497-509
pubmed: 13428781
Nat Commun. 2017 Dec 12;8(1):2068
pubmed: 29233977
Cancer Cell. 2016 Jul 11;30(1):161-175
pubmed: 27411590
J Biol Chem. 2003 Sep 5;278(36):33928-35
pubmed: 12821666
Biochim Biophys Acta. 2013 May;1827(5):598-611
pubmed: 23291191
Biochim Biophys Acta. 2015 Feb;1851(2):152-62
pubmed: 25463480
J Lipid Res. 2013 Nov;54(11):2988-97
pubmed: 23964120
Nat Rev Drug Discov. 2016 Nov 3;15(11):745-746
pubmed: 27807356
Hepatology. 2008 Apr;47(4):1191-9
pubmed: 18318442
Hepatology. 2014 Feb;59(2):471-82
pubmed: 23913408
J Lipid Res. 1997 Jul;38(7):1482-9
pubmed: 9254073
Gastroenterology. 2013 Nov;145(5):1076-87
pubmed: 23916847
Hepatology. 2003 Oct;38(4):999-1007
pubmed: 14512887
Int J Cancer. 1998 Mar 2;75(5):787-93
pubmed: 9495250
Nat Commun. 2017 May 08;8:15111
pubmed: 28480888
Biochim Biophys Acta. 2010 Dec;1797(12):1910-6
pubmed: 20937244
PLoS One. 2013 Jul 30;8(7):e70062
pubmed: 23936142
Cell Death Dis. 2018 Sep 20;9(10):958
pubmed: 30237481
Mol Med. 2012 Jul 18;18:744-52
pubmed: 22415010
J Hepatol. 2000 Dec;33(6):907-14
pubmed: 11131452
Hepatology. 2009 Dec;50(6):1796-808
pubmed: 19816994
Nat Methods. 2009 May;6(5):359-62
pubmed: 19377485
Gastroenterology. 2018 Sep;155(3):629-647
pubmed: 30012333
J Hepatol. 2015 Mar;62(3):673-81
pubmed: 25457203
Hepatology. 2014 May;59(5):1830-9
pubmed: 24115079
Hepatology. 2017 Feb;65(2):694-709
pubmed: 28035772
Mol Cell Biochem. 2002 Nov;240(1-2):1-8
pubmed: 12487366
J Biol Chem. 1961 Jan;236:177-83
pubmed: 13716069
Gastroenterology. 2012 Sep;143(3):787-798.e13
pubmed: 22687285