Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma.
Animals
CCAAT-Enhancer-Binding Protein-beta
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Line
Cell Transformation, Neoplastic
/ drug effects
Clofazimine
/ pharmacology
Diet, High-Fat
/ adverse effects
Disease Progression
Gene Silencing
Humans
Lipogenesis
/ drug effects
Liver Neoplasms
/ genetics
Male
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease
/ genetics
Obesity
/ etiology
Peptide Initiation Factors
/ antagonists & inhibitors
Protein Biosynthesis
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 08 2021
12 08 2021
Historique:
received:
08
07
2020
accepted:
24
07
2021
entrez:
13
8
2021
pubmed:
14
8
2021
medline:
31
8
2021
Statut:
epublish
Résumé
A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPβ, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.
Identifiants
pubmed: 34385447
doi: 10.1038/s41467-021-25195-1
pii: 10.1038/s41467-021-25195-1
pmc: PMC8361022
doi:
Substances chimiques
CCAAT-Enhancer-Binding Protein-beta
0
Peptide Initiation Factors
0
eIF-6
0
Clofazimine
D959AE5USF
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4878Informations de copyright
© 2021. The Author(s).
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