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Brina, Daniela; Miluzio, Annarita; Ricciardi, Sara; Clarke, Kim; Davidsen, Peter K.; Viero, Gabriella; Tebaldi, Toma; Offenhaeuser, Nina; Rozman, Jan; Rathkolb, Birgit; Neschen, Susanne; Klingenspor, Martin; Wolf, Eckhard; Gailus-Durner, Valerie; Fuchs, Helmut; de Angelis, Martin Hrabe; Quattrone, Alessandro; Falciani, Francesco; Biffo, Stefano (2015): eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription. In: Nature Communications, Vol. 6, 8261
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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/EBP beta, C/EBP delta 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.