SREBPs suppress IRS-2-mediated insulin signalling in the liver

Nature Cell Biology volume 6, pages351–357(2004)Cite this article

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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Figure 1: An inverse correlation between hepatic IRS-2 and SREBP-1 gene expression.
Figure 2: Nuclear SREBPs reduce IRS-2 expression and insulin signalling in primary hepatocytes.
Figure 3: Nuclear SREBP-1c and SREBP-1a inhibit IRS-2 promoter activity competing with FKHs.
Figure 4: SREBP-1c in hepatic nuclear extracts dominates binding to the IRS-2-SRE.

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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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Affiliations

  1. Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tennodai, Tsukuba, 305-8575, Ibaraki, Japan

    Tomohiro Ide, Takashi Matsuzaka, Masanori Nakakuki, Takashi Yamamoto, Akimitsu Takahashi, Hiroaki Suzuki, Hirohito Sone, Hideo Toyoshima & Nobuhiro Yamada

  2. Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennodai, Tsukuba, 305-8575, Ibaraki, Japan

    Hitoshi Shimano, Naoya Yahagi, Yoshimi Nakagawa & Akiyoshi Fukamizu

  3. Institute of Applied Biochemistry, University of Tsukuba, Tennodai, Tsukuba, 305-8575, Ibaraki, Japan

    Akiyoshi Fukamizu

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  1. Tomohiro Ide
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  2. Hitoshi Shimano
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  3. Naoya Yahagi
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  4. Takashi Matsuzaka
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Correspondence to Hitoshi Shimano.

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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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