Abstract
Insulin receptor substrate 2 (IRS-2) is the main mediator of insulin signalling in the liver, controlling insulin sensitivity. Sterol regulatory element binding proteins (SREBPs) have been established as transcriptional regulators of lipid synthesis. Here, we show that SREBPs directly repress transcription of IRS-2 and inhibit hepatic insulin signalling. The IRS-2 promoter is activated by forkhead proteins through an insulin response element (IRE). Nuclear SREBPs effectively replace and interfere in the binding of these transactivators, resulting in inhibition of the downstream PI(3)K/Akt pathway, followed by decreased glycogen synthesis. These data suggest a molecular mechanism for the physiological switching from glycogen synthesis to lipogenesis and hepatic insulin resistance that is associated with hepatosteatosis.
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Acknowledgements
We are grateful to M.S. Brown and J.L. Goldstein for continuous support of the SREBP projects. We also thank H. Kurose for technical support with the adenoviral vectors, and A.H. Hasty for critical reading of the manuscript. We acknowledge S. Ishibashi, T. Gotoda, J. Osuga and K. Murakami for helpful discussions. This work was supported by grants-in-aid from the Ministry of Science, Education, Culture and Technology of Japan.
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Ide, T., Shimano, H., Yahagi, N. et al. SREBPs suppress IRS-2-mediated insulin signalling in the liver. Nat Cell Biol 6, 351–357 (2004). https://doi.org/10.1038/ncb1111
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DOI: https://doi.org/10.1038/ncb1111
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