Letter abstract
Nature Cell Biology 6, 351 - 357 (2004)
Published online: 14 March 2004 | doi:10.1038/ncb1111
SREBPs suppress IRS-2-mediated insulin signalling in the liver
Tomohiro Ide1, Hitoshi Shimano2, Naoya Yahagi2, Takashi Matsuzaka1, Masanori Nakakuki1, Takashi Yamamoto1, Yoshimi Nakagawa2, Akimitsu Takahashi1, Hiroaki Suzuki1, Hirohito Sone1, Hideo Toyoshima1, Akiyoshi Fukamizu2,3 & Nobuhiro Yamada1
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.
- Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
- Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
- Institute of Applied Biochemistry, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
Correspondence to: Hitoshi Shimano2 e-mail: shimano-tky@umin.ac.jp
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