Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation.
Adult
Aged
Animals
Datasets as Topic
Diet, High-Fat
/ adverse effects
Disease Models, Animal
Fatty Acids
/ metabolism
Female
HSP40 Heat-Shock Proteins
/ antagonists & inhibitors
Hepatocytes
/ cytology
Humans
Liver
/ cytology
Male
Middle Aged
Mitochondria
/ drug effects
Mitochondrial Proteins
/ antagonists & inhibitors
Molecular Chaperones
/ antagonists & inhibitors
Nanoparticles
/ administration & dosage
Non-alcoholic Fatty Liver Disease
/ drug therapy
Oxidation-Reduction
/ drug effects
Primary Cell Culture
RNA, Small Interfering
/ administration & dosage
RNA-Seq
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 07 2020
03 07 2020
Historique:
received:
19
06
2019
accepted:
04
06
2020
entrez:
5
7
2020
pubmed:
6
7
2020
medline:
29
8
2020
Statut:
epublish
Résumé
Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate β-oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD.
Identifiants
pubmed: 32620763
doi: 10.1038/s41467-020-16991-2
pii: 10.1038/s41467-020-16991-2
pmc: PMC7334216
doi:
Substances chimiques
DNAJC15 protein, human
0
Fatty Acids
0
HSP40 Heat-Shock Proteins
0
Mcj protein, mouse
0
Mitochondrial Proteins
0
Molecular Chaperones
0
RNA, Small Interfering
0
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
3360Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM103496
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023108
Pays : United States
Organisme : NIDDK NIH HHS
ID : R41 DK112429
Pays : United States
Organisme : NIDDK NIH HHS
ID : R41 DK117760
Pays : United States
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