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

• Published in: Nature communications Vol. 6; no. 1; p. 8261
• Main Authors: Brina, Daniela, Miluzio, Annarita, Ricciardi, Sara, Clarke, Kim, Davidsen, Peter K., Viero, Gabriella, Tebaldi, Toma, Offenhäuser, Nina, Rozman, Jan, Rathkolb, Birgit, Neschen, Susanne, Klingenspor, Martin, Wolf, Eckhard, Gailus-Durner, Valerie, Fuchs, Helmut, Hrabe de Angelis, Martin, Quattrone, Alessandro, Falciani, Francesco, Biffo, Stefano
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.09.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13/106; 38/39; 38/61; 3T3 Cells; 631/337/574; 631/80/86/2367; 64/60; 692/308; 692/699/317; 82/80; Acetylation; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Adipocytes - metabolism; Adipogenesis - genetics; Animals; Biology; Blood glucose; Blotting, Western; Cancer; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; CCAAT-Enhancer-Binding Protein-delta - genetics; CCAAT-Enhancer-Binding Protein-delta - metabolism; Cell cycle; Cholesterol; Diabetes; Electrophoresis, Polyacrylamide Gel; Fatty Acid Synthases - genetics; Fatty Acid Synthases - metabolism; Fatty Acids; Gene expression; Gene Expression Regulation; Gene Knockdown Techniques; Glucose; Glucose - metabolism; Glucose Tolerance Test; Glycogen - metabolism; Glycolysis; Glycolysis - genetics; HEK293 Cells; Hepatocytes - metabolism; Histone Code; Humanities and Social Sciences; Humans; Insulin; Insulin resistance; Insulin Resistance - genetics; Kinases; Lactic Acid - metabolism; Lipid metabolism; Lipid Metabolism - genetics; Lipids; Lipogenesis - genetics; Liver; Liver - diagnostic imaging; Liver - metabolism; Mesenchymal Stem Cells; Metabolic syndrome; Mice; multidisciplinary; Oxidation-Reduction; Peptide Initiation Factors - genetics; Peptide Initiation Factors - metabolism; Phosphorylation; Physiology; Protein Biosynthesis - genetics; Proteins; Radiography; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Transcription, Genetic - genetics; Triglycerides
• DOI: 10.1038/ncomms9261
• ISSN: 2041-1723

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. Insulin enhances mRNA translation via the translation initiation factor eIF6. Here, Brina et al . show that insulin-mediated activation of eIF6 is associated with the selective translation of genes involved in glycolysis and lipid synthesis with characteristic G/C-rich and uORF sequences in their mRNA.