Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma.

Abstract

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.

• Authors: Alessandra Scagliola, Annarita Miluzio, Gabriele Ventura, Stefania Oliveto, Chiara Cordiglieri, Nicola Manfrini, Delia Cirino, Sara Ricciardi, Luca Valenti, Guido Baselli, Roberta D'Ambrosio, Marco Maggioni, Daniela Brina, Alberto Bresciani, Stefano Biffo
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 4878 (08 12 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34385447 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• CCAAT-Enhancer-Binding Protein-beta
• Peptide Initiation Factors
• eIF-6
• Clofazimine

Topics

• Animals
• CCAAT-Enhancer-Binding Protein-beta (genetics, metabolism)
• Carcinoma, Hepatocellular (genetics, metabolism)
• Cell Line
• Cell Transformation, Neoplastic (drug effects, genetics, metabolism)
• Clofazimine (pharmacology)
• Diet, High-Fat (adverse effects)
• Disease Progression
• Gene Silencing
• Humans
• Lipogenesis (drug effects, genetics)
• Liver Neoplasms (genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• Obesity (etiology, genetics, metabolism)
• Peptide Initiation Factors (antagonists & inhibitors, genetics, metabolism)
• Protein Biosynthesis (genetics)