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.

eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription / D. Brina, A. Miluzio, S. Ricciardi, K. Clarke, P.K. Davidsen, G. Viero, T. Tebaldi, N. Offenhäuser, J. Rozman, B. Rathkolb, S. Neschen, M. Klingenspor, E. Wolf, V. Gailus-Durner, H. Fuchs, M. Hrabe De Angelis, A. Quattrone, F. Falciani, S. Biffo. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 6(2015).

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

A. Miluzio
Secondo
;
S. Ricciardi;S. Biffo
Ultimo
2015

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.
Biochemistry, Genetics and Molecular Biology (all); Chemistry (all); Physics and Astronomy (all)
Settore BIO/06 - Anatomia Comparata e Citologia
http://www.nature.com/ncomms/index.html
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/336987
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