title: eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription.
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.
authors.affiliation: INGM, 'Romeo ed Enrica Invernizzi', 20122 Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brina
authors.affiliation: INGM, 'Romeo ed Enrica Invernizzi', 20122 Milano, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Miluzio
authors.affiliation: INGM, 'Romeo ed Enrica Invernizzi', 20122 Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ricciardi
authors.affiliation: Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Davidsen
authors.affiliation: Institute of Biophysics, 38123 Trento, Italy.|Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Viero
authors.affiliation: Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Toma
authors.initials: T
authors.lastname: Tebaldi
authors.affiliation: IFOM Foundation, 20139 Milano, Italy.
authors.forename: Nina
authors.initials: N
authors.lastname: Offenhäuser
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.|Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University, 81377 Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neschen
authors.affiliation: Else Kröner-Fresenius Center, Technische Universität München, 85354 Freising, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University, 81377 Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.|Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising, Germany.|German Center for Diabetes Research, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabe de Angelis
authors.affiliation: Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Quattrone
authors.affiliation: Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani
authors.affiliation: INGM, 'Romeo ed Enrica Invernizzi', 20122 Milano, Italy.|Department of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
mesh_terms: D016475:3T3 Cells; D000107:Acetylation; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D042421:Histone Code; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D019344:Lactic Acid / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D059630:Mesenchymal Stem Cells; D051379:Mice; D010084:Oxidation-Reduction; D010448:Peptide Initiation Factors / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D011859:Radiography; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C081452:Atf4 protein, mouse; D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; C497253:Cebpd protein, mouse; D005227:Fatty Acids; C115811:Itgb4bp protein, mouse; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D051743:CCAAT-Enhancer-Binding Protein-delta; D051701:Activating Transcription Factor 4; D019344:Lactic Acid; D006003:Glycogen; D064429:Fatty Acid Synthases; D005947:Glucose