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.
Highlights
Insulin regulates glycaemia, lipogenesis and increases mRNA translation
The insensitivity to rapamycin inhibition of cells with mutated RAS suggests that other initiation factors act independently from mTOR among them, eIF4E and eukaryotic initiation factor 6 (eIF6). eIF4E phosphorylation is regulated by the RAS-Mnk1/2 cascade and, in the context of cancer, constitutive eIF4E activation is associated with tumour progression14,15. eIF6 is an initiation factor acting independently from mTOR16. eIF6 heterozygosity restrains tumourigenesis and leads to a striking increased survival in a mouse model of Em-Myc lymphoma17. eIF6 amplification occurs in luminal breast cancer18. eIF6 is an anti-association factor that prevent formation of inactive 80S complex, by binding to 60S. eIF6 phosphorylation is stimulated by phorbol esters inducing protein kinase C (PKC) activation and in response to insulin[20]
Results eIF6 is required for efficient lipid synthesis in vivo. eIF6 heterozygous cells express 50% eIF6 compared with wild type, have normal basal translation, but impaired insulinstimulated translation22. eIF6 het mice are healthy, leaner[22] and resistant to Myc-induced lymphomagenesis compared with wt ones[17]
Summary
Nonalcoholic fatty liver disease is the most common liver disorder in the Western world[2] and is universally associated with hepatic insulin resistance, which increases the risk of impaired control of fasting glycaemia and of type 2 diabetes[3]. The insensitivity to rapamycin inhibition of cells with mutated RAS suggests that other initiation factors act independently from mTOR among them, eIF4E and eIF6. The protective effects of eIF6 depletion on tumour growth and the specific action of eIF6 on insulin-stimulated translation suggest that eIF6 and 60S availability control the translation of specific mRNAs. eIF6 has been reported to regulate miRNA-based repression, but this role has not been confirmed by further studies[23].
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