Format

Send to

Choose Destination
Nat Commun. 2015 Sep 18;6:8261. doi: 10.1038/ncomms9261.

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

Author information

1
INGM, 'Romeo ed Enrica Invernizzi', 20122 Milano, Italy.
2
Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
3
Institute of Biophysics, 38123 Trento, Italy.
4
Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
5
IFOM Foundation, 20139 Milano, Italy.
6
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
7
Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University, 81377 Munich, Germany.
8
Else Kröner-Fresenius Center, Technische Universität München, 85354 Freising, Germany.
9
Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising, Germany.
10
German Center for Diabetes Research, 85764 Neuherberg, Germany.
11
Department of Biosciences, University of Milan, 20133 Milan, Italy.

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.

PMID:
26383020
PMCID:
PMC4595657
DOI:
10.1038/ncomms9261
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Secondary source ID, Grant support

Publication type

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center