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eIF6 – Target for obesity, T2D and cancer

Insulin controls glycaemia, regulates lipogenesis, and increases mRNA translation. The role of insulin-regulated translation is unknown so far but cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. Therefore, to obtain more detailed insights into the function of eIF6, mice heterozygous for eIF6 and wildtype littermates were investigated. The following changes were observed during the comparative analysis. eIF6 het mice are healthy, but leaner and resistant to Myc-induced lymphomagenesis compared with wt mice. The analysis of a cohort of wt and heterozygous eIF6 mice in the GMC revealed a broad range of interesting results:

  • Clinical chemistry and glucose tolerance test (GTT).
    eIF6 het mice had normal response to glucose load. In fed conditions eIF6 het mice had reduced blood cholesterol levels, triglycerides, and not esterified fatty acids. Blood glucose was slightly lower in both fasted and fed conditions. Insulin levels were lower in fasting conditions. All other parameters in fasting were identical between wt and het mice.
  • Hepatic function.
    Markers for hepatic function were identical between wt and het mice, suggesting overall normal liver function.

In liver, insulin stimulates glucose storage through stimulation of glycogen synthesis. The analysis showed that eIF6 het had glycogen levels identical to wt mice. Liver ATP levels were lower in eIF6 het mice compared to wt. The analysis of liver polysome peaks as an indicator of initiation of translation after feeding showed that polysomes from eIF6 het mice were lower than in wt, consistent with reduced initiation of translation, in vivo after feeding. During fasting, eIF6 het mice displayed a polysome profile similar to wt ones.

Taken together, the results showed that eIF6 mice have impaired insulin-stimulated translation, reduction of blood and liver lipid levels without impairment of blood glucose control and glycogen synthesis.

In order to define whether the translational deficit on insulin stimulation has an impact in pathological conditions, the scientists tested the response of eIF6 het mice to a high-fat diet (HFD) regimen and found that eIF6 het mice had a reduced weight gain during HFD compared with wt controls but no substantial difference in glucose tolerance and insulin levels at time 0. Nonetheless, insulin levels were significantly lower in het mice compared with wt mice after 120 min from glucose injection. However, an insulin tolerance test (ITT) showed that eIF6 het mice responded better to insulin. Following the HFD, eIF6 het mice showed increased liver-X-ray attenuation in the liver and decreased triglycerides (TG) levels compared with wt mice demonstrating reduced hepatic lipid content. At autopsy, eIF6 het livers were less enlarged.

To transfer this knowledge to humans, the scientists analyzed whether a relationship between eIF6 levels and insulin resistance could be found in humans. They found that eIF6 expression negatively correlates with insulin sensitivity, as an independent factor.
In conclusion, the data demonstrate that the impairment of translation due to eIF6 depletion affects liver lipid metabolism leading to reduced susceptibility to hepatic lipid accumulation.

Further experiments, e.g. in cell culture, revealed more interesting correlations. 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, Brina et al propose that eIF6 could be a therapeutic target for these diseases.

Daniela Brina, Annarita Miluzio, Sara Ricciardi, Kim Clarke, Peter K. Davidsen, Gabriella Viero, Toma Tebaldi, Nina Offenhäuser, Jan Rozman, Birgit Rathkolb, Susanne Neschen, Martin Klingenspor, Eckhard Wolf, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Alessandro Quattrone, Francesco Falciani & Stefano Biffo, (2015): eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription. NATURE COMMUNICATIONS | 6:8261 | DOI: 10.1038/ncomms9261 |www.nature.com/naturecommunications