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

Author

Listed:
  • 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
    Centre for Integrative Biology, University of Trento)

  • Toma Tebaldi

    (Centre for Integrative Biology, University of Trento)

  • Nina Offenhäuser

    (IFOM Foundation
    Present address: Cogentech, 20139 Milano, Italy)

  • Jan Rozman

    (German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich)

  • Birgit Rathkolb

    (German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
    Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University)

  • 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
    Center of Life and Food Sciences Weihenstephan, Technische Universität München
    German Center for Diabetes Research)

  • 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’
    University of Milan)

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.

Suggested Citation

  • Daniela Brina & Annarita Miluzio & Sara Ricciardi & Kim Clarke & Peter K. Davidsen & Gabriella Viero & Toma Tebaldi & Nina Offenhäuser & Jan Rozman & Birgit Rathkolb & Susanne Neschen & Martin Klingen, 2015. "eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9261
    DOI: 10.1038/ncomms9261
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