eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription

Daniela Brina, Annarita Miluzio, Sara Ricciardi, Kim Clarke, Peter K. Davidsen, Gabriella Viero, Toma Tebaldi, Nina Offenhäuser, Jan Rozman, Birgit Rathkolb, Susanne Neschen, Martin Klingenspor, Eckhard Wolf, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe De Angelis, Alessandro Quattrone, Francesco Falciani, Stefano Biffo

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Insulin regulates glycaemia, lipogenesis and increases mRNA translation. Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. The role of insulin-regulated translation is unknown. Here we show that reduction of insulin-regulated translation in mice heterozygous for eIF6 results in normal glycaemia, but less blood cholesterol and triglycerides. eIF6 controls fatty acid synthesis and glycolysis in a cell autonomous fashion. eIF6 acts by exerting translational control of adipogenic transcription factors like C/EBPβ, C/EBPδ and ATF4 that have G/C rich or uORF sequences in their 5′ UTR. The outcome of the translational activation by eIF6 is a reshaping of gene expression with increased levels of lipogenic and glycolytic enzymes. Finally, eIF6 levels modulate histone acetylation and amounts of rate-limiting fatty acid synthase (Fasn) mRNA. Since obesity, type 2 diabetes, and cancer require a Fasn-driven lipogenic state, we propose that eIF6 could be a therapeutic target for these diseases.

Original languageEnglish
Article number8261
JournalNature Communications
Volume6
DOIs
StatePublished - 18 Sep 2015

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