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 and Stefano Biffo ()
Additional contact information
Daniela Brina: INGM, ‘Romeo ed Enrica Invernizzi’
Annarita Miluzio: INGM, ‘Romeo ed Enrica Invernizzi’
Sara Ricciardi: INGM, ‘Romeo ed Enrica Invernizzi’
Kim Clarke: Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool
Peter K. Davidsen: Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool
Gabriella Viero: Institute of Biophysics
Toma Tebaldi: Centre for Integrative Biology, University of Trento
Nina Offenhäuser: IFOM Foundation
Jan Rozman: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Birgit Rathkolb: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Susanne Neschen: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Martin Klingenspor: Else Kröner-Fresenius Center, Technische Universität München
Eckhard Wolf: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University
Valerie Gailus-Durner: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Helmut Fuchs: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Martin Hrabe de Angelis: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Alessandro Quattrone: Centre for Integrative Biology, University of Trento
Francesco Falciani: Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool
Stefano Biffo: INGM, ‘Romeo ed Enrica Invernizzi’

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9261

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