SREBPs suppress IRS-2-mediated insulin signalling in the liver.
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.
Ide
Tomohiro
T
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
Shimano
Hitoshi
H
Yahagi
Naoya
N
Matsuzaka
Takashi
T
Nakakuki
Masanori
M
Yamamoto
Takashi
T
Nakagawa
Yoshimi
Y
Takahashi
Akimitsu
A
Suzuki
Hiroaki
H
Sone
Hirohito
H
Toyoshima
Hideo
H
Fukamizu
Akiyoshi
A
Yamada
Nobuhiro
N
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000235:genetics; D051858:Forkhead Transcription Factors; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C484091:insulin response element binding protein, rat; D006003:Glycogen; D019869:Phosphatidylinositol 3-Kinases