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Brina, D.* ; Miluzio, A.* ; Ricciardi, S.* ; Clarke, K.* ; Davidsen, P.K.* ; Viero, G.* ; Tebaldi, T.* ; Offenhäuser, N.* ; Rozman, J. ; Rathkolb, B. ; Neschen, S. ; Klingenspor, M. ; Wolf, E. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Quattrone, A.* ; Falciani, F.* ; Biffo, S.*

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

Nat. Commun. 6:8261 (2015)

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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.

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