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.

Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma / A. Scagliola, A. Miluzio, G. Ventura, S. Oliveto, C. Cordiglieri, N. Manfrini, D. Cirino, S. Ricciardi, L. Valenti, G. Baselli, R. D'Ambrosio, M. Maggioni, D. Brina, A. Bresciani, S. Biffo. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 12:1(2021 Aug 12), pp. 4878.1-4878.16. [10.1038/s41467-021-25195-1]

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

A. Scagliola
Co-primo
;
A. Miluzio
Co-primo
;
S. Oliveto;N. Manfrini;S. Ricciardi;L. Valenti;G. Baselli;S. Biffo
Ultimo
2021

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.
Animals; CCAAT-Enhancer-Binding Protein-beta; Carcinoma, Hepatocellular; Cell Line; Cell Transformation, Neoplastic; Clofazimine; Diet, High-Fat; Disease Progression; Gene Silencing; Humans; Lipogenesis; Liver Neoplasms; Male; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Initiation Factors; Protein Biosynthesis
Settore BIO/06 - Anatomia Comparata e Citologia
7PQ_ERC14SBIFF_M - Noncoding and Translational Modulation of Gene Expression and Epigenetic Changes - BIFFO, STEFANO - 7PQ_ERC - 7 Programma Quadro_European Research Coucil - 2014
Article (author)
File in questo prodotto:
File Dimensione Formato  
41467_2021_Article_25195.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 9.67 MB
Formato Adobe PDF
9.67 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/882241
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 8
social impact