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

Brina D, Miluzio A, Ricciardi S, Clarke K, Davidsen PK, Viero G, Tebaldi T, Offenhäuser N, Rozman J, Rathkolb B, Neschen S, Klingenspor M, Wolf E, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Quattrone A, Falciani F, Biffo S - Nat Commun (2015)

Bottom Line: Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin.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.

View Article: PubMed Central - PubMed

Affiliation: INGM, 'Romeo ed Enrica Invernizzi', 20122 Milano, 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.

No MeSH data available.


Related in: MedlinePlus

eIF6 depletion impairs polysome formation in the liver after feeding, reduces lipidemia, protects from HFD and liver steatosis.All graphs, black, wt; red, eIF6 het mice (a) Representative liver polysomal profiles of wt (black) and eIF6 het (red, +/−) show reduced polysomes in het after overnight fasting and 4 h refeeding. Experiment repeated at least five times. (b) GTT is normal in eIF6 het (red) compared with wt. N=7. (c,d) Cholesterol and triglycerides levels are reduced in blood of eIF6 het compared with wt ones (N=10). (e) Liver triglyceride content is reduced in eIF6 het mice (N=4). (f) ATP liver content is reduced in eIF6 het. N=3. (g) eIF6 het mice are protected from HFD: body weight gain is reduced in eIF6 het mice compared with wt. N=10. Top bars show absolute body weight gain. Lower graph, body weight. (h) GTT eIF6 het mice have lower insulinaemia at 2 h after glucose injection. N=10. (i) ITT (AUC ITT, area under curve) shows partial amelioration of diet-induced insulin resistance. N=5 (j,k). Increased liver-X-ray attenuation (N=8) indicating reduced fat deposition in the liver (j) confirmed by autoptic liver triglyceride content on separate animals (N=5) (k). (i) In humans, eIF6 levels inversely correlate with insulin sensitivity, as measured by HOMA-IR. In all panels, data are represented as mean±s.d. Statistical P values were calculated by two-tailed t-test (*P value ≤0.05).
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f1: eIF6 depletion impairs polysome formation in the liver after feeding, reduces lipidemia, protects from HFD and liver steatosis.All graphs, black, wt; red, eIF6 het mice (a) Representative liver polysomal profiles of wt (black) and eIF6 het (red, +/−) show reduced polysomes in het after overnight fasting and 4 h refeeding. Experiment repeated at least five times. (b) GTT is normal in eIF6 het (red) compared with wt. N=7. (c,d) Cholesterol and triglycerides levels are reduced in blood of eIF6 het compared with wt ones (N=10). (e) Liver triglyceride content is reduced in eIF6 het mice (N=4). (f) ATP liver content is reduced in eIF6 het. N=3. (g) eIF6 het mice are protected from HFD: body weight gain is reduced in eIF6 het mice compared with wt. N=10. Top bars show absolute body weight gain. Lower graph, body weight. (h) GTT eIF6 het mice have lower insulinaemia at 2 h after glucose injection. N=10. (i) ITT (AUC ITT, area under curve) shows partial amelioration of diet-induced insulin resistance. N=5 (j,k). Increased liver-X-ray attenuation (N=8) indicating reduced fat deposition in the liver (j) confirmed by autoptic liver triglyceride content on separate animals (N=5) (k). (i) In humans, eIF6 levels inversely correlate with insulin sensitivity, as measured by HOMA-IR. In all panels, data are represented as mean±s.d. Statistical P values were calculated by two-tailed t-test (*P value ≤0.05).

Mentions: eIF6 heterozygous (het) cells express 50% eIF6 compared with wild type (wt), have normal basal translation, but impaired insulin-stimulated translation22. eIF6 het mice are healthy, leaner22 and resistant to Myc-induced lymphomagenesis compared with wt ones17. We employed a cohort of wt and het mice, n=40, in a pure C57BL/6 genetic background (Supplementary Fig. 1a,b). We analysed liver polysome peaks as an indicator of initiation of translation, in vivo, after feeding. Polysomes from eIF6 het mice were lower than in wt, consistent with reduced initiation of translation, in vivo (Fig. 1a) after feeding. During fasting, eIF6 het mice displayed a polysome profile similar to wt ones (Supplementary Fig. 1c). This model therefore allows the analysis of the physiological role of translation in vivo, after feeding. We first asked whether glycemic control is maintained in conditions of eIF6 deficiency. To evaluate glucose tolerance, we performed a glucose tolerance test (GTT). We found that eIF6 het mice had normal response to glucose load (Fig. 1b). A broad clinical chemistry analysis revealed that in refed conditions eIF6 het mice had reduced blood cholesterol levels (Fig. 1c), triglycerides (Fig. 1d), liver triglycerydes (Fig. 1e), non-essential fatty acids (Supplementary Fig. 1d). Glycaemia was slightly lower in both fasted and refed conditions (Supplementary Fig. 1d). Insulin levels were lower in fasting conditions (Supplementary Fig. 1d). All other parameters in fasting were identical between wt and het mice (Supplementary Fig. 1d). Markers for hepatic function were identical between wt and het mice, suggesting overall normal hepatic function (Supplementary Fig. 1e). In liver, insulin stimulates glucose storage through stimulation of glycogen synthesis. We found that eIF6 het had glycogen levels identical to wt mice (Supplementary Fig. 1f,g). Liver ATP levels were lower in eIF6 het mice compared to wt (Fig. 1f). In conclusion, eIF6 mice have impaired insulin-stimulated translation22 accompanied by reduction of blood and liver lipid levels without impairment of glucose blood control and glycogen synthesis.


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

Brina D, Miluzio A, Ricciardi S, Clarke K, Davidsen PK, Viero G, Tebaldi T, Offenhäuser N, Rozman J, Rathkolb B, Neschen S, Klingenspor M, Wolf E, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Quattrone A, Falciani F, Biffo S - Nat Commun (2015)

eIF6 depletion impairs polysome formation in the liver after feeding, reduces lipidemia, protects from HFD and liver steatosis.All graphs, black, wt; red, eIF6 het mice (a) Representative liver polysomal profiles of wt (black) and eIF6 het (red, +/−) show reduced polysomes in het after overnight fasting and 4 h refeeding. Experiment repeated at least five times. (b) GTT is normal in eIF6 het (red) compared with wt. N=7. (c,d) Cholesterol and triglycerides levels are reduced in blood of eIF6 het compared with wt ones (N=10). (e) Liver triglyceride content is reduced in eIF6 het mice (N=4). (f) ATP liver content is reduced in eIF6 het. N=3. (g) eIF6 het mice are protected from HFD: body weight gain is reduced in eIF6 het mice compared with wt. N=10. Top bars show absolute body weight gain. Lower graph, body weight. (h) GTT eIF6 het mice have lower insulinaemia at 2 h after glucose injection. N=10. (i) ITT (AUC ITT, area under curve) shows partial amelioration of diet-induced insulin resistance. N=5 (j,k). Increased liver-X-ray attenuation (N=8) indicating reduced fat deposition in the liver (j) confirmed by autoptic liver triglyceride content on separate animals (N=5) (k). (i) In humans, eIF6 levels inversely correlate with insulin sensitivity, as measured by HOMA-IR. In all panels, data are represented as mean±s.d. Statistical P values were calculated by two-tailed t-test (*P value ≤0.05).
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Related In: Results  -  Collection

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f1: eIF6 depletion impairs polysome formation in the liver after feeding, reduces lipidemia, protects from HFD and liver steatosis.All graphs, black, wt; red, eIF6 het mice (a) Representative liver polysomal profiles of wt (black) and eIF6 het (red, +/−) show reduced polysomes in het after overnight fasting and 4 h refeeding. Experiment repeated at least five times. (b) GTT is normal in eIF6 het (red) compared with wt. N=7. (c,d) Cholesterol and triglycerides levels are reduced in blood of eIF6 het compared with wt ones (N=10). (e) Liver triglyceride content is reduced in eIF6 het mice (N=4). (f) ATP liver content is reduced in eIF6 het. N=3. (g) eIF6 het mice are protected from HFD: body weight gain is reduced in eIF6 het mice compared with wt. N=10. Top bars show absolute body weight gain. Lower graph, body weight. (h) GTT eIF6 het mice have lower insulinaemia at 2 h after glucose injection. N=10. (i) ITT (AUC ITT, area under curve) shows partial amelioration of diet-induced insulin resistance. N=5 (j,k). Increased liver-X-ray attenuation (N=8) indicating reduced fat deposition in the liver (j) confirmed by autoptic liver triglyceride content on separate animals (N=5) (k). (i) In humans, eIF6 levels inversely correlate with insulin sensitivity, as measured by HOMA-IR. In all panels, data are represented as mean±s.d. Statistical P values were calculated by two-tailed t-test (*P value ≤0.05).
Mentions: eIF6 heterozygous (het) cells express 50% eIF6 compared with wild type (wt), have normal basal translation, but impaired insulin-stimulated translation22. eIF6 het mice are healthy, leaner22 and resistant to Myc-induced lymphomagenesis compared with wt ones17. We employed a cohort of wt and het mice, n=40, in a pure C57BL/6 genetic background (Supplementary Fig. 1a,b). We analysed liver polysome peaks as an indicator of initiation of translation, in vivo, after feeding. Polysomes from eIF6 het mice were lower than in wt, consistent with reduced initiation of translation, in vivo (Fig. 1a) after feeding. During fasting, eIF6 het mice displayed a polysome profile similar to wt ones (Supplementary Fig. 1c). This model therefore allows the analysis of the physiological role of translation in vivo, after feeding. We first asked whether glycemic control is maintained in conditions of eIF6 deficiency. To evaluate glucose tolerance, we performed a glucose tolerance test (GTT). We found that eIF6 het mice had normal response to glucose load (Fig. 1b). A broad clinical chemistry analysis revealed that in refed conditions eIF6 het mice had reduced blood cholesterol levels (Fig. 1c), triglycerides (Fig. 1d), liver triglycerydes (Fig. 1e), non-essential fatty acids (Supplementary Fig. 1d). Glycaemia was slightly lower in both fasted and refed conditions (Supplementary Fig. 1d). Insulin levels were lower in fasting conditions (Supplementary Fig. 1d). All other parameters in fasting were identical between wt and het mice (Supplementary Fig. 1d). Markers for hepatic function were identical between wt and het mice, suggesting overall normal hepatic function (Supplementary Fig. 1e). In liver, insulin stimulates glucose storage through stimulation of glycogen synthesis. We found that eIF6 het had glycogen levels identical to wt mice (Supplementary Fig. 1f,g). Liver ATP levels were lower in eIF6 het mice compared to wt (Fig. 1f). In conclusion, eIF6 mice have impaired insulin-stimulated translation22 accompanied by reduction of blood and liver lipid levels without impairment of glucose blood control and glycogen synthesis.

Bottom Line: Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin.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.

View Article: PubMed Central - PubMed

Affiliation: INGM, 'Romeo ed Enrica Invernizzi', 20122 Milano, 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.

No MeSH data available.


Related in: MedlinePlus