Regulation of insulin-response element binding protein-1 in obesity and diabetes: potential role in impaired insulin-induced gene transcription.
One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown. In this study, we show that IRE-BP1 interacts with the insulin response sequence of the IGF-I, IGFBP-1, and IGFBP-3 genes using chromatin immunoprecipitation assay. Furthermore, activation by IRE-BP1 is sequence specific and mimics that of the insulin effect on gene transcription. Tissue expression of IRE-BP1 is 50- to 200-fold higher in classical insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of insulin-mediated phosphatidylinositol-3 kinase signaling. Therefore, in diabetes and obesity, the mechanisms involved in reducing the transactivation of the insulin response sequence by IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent DNA binding. Our study supports the notion that IRE-BP1 may be relevant to the action of insulin in vivo and may play a role in the development of insulin resistance and diabetes.
Department of Medicine, Division of Endocrinology & Metabolism, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Building, Room 119E, Louisville, Kentucky 40202, USA.
Jaspreet
J
Chahal
Ching-Chu
CC
Chen
Madhavi J
MJ
Rane
Joseph P
JP
Moore
Michelle T
MT
Barati
Ying
Y
Song
Betty C
BC
Villafuerte
D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002843:Chromatin / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D035941:Iron Regulatory Protein 1 / Q000235:genetics* / Q000378:metabolism*; D008113:Liver Neoplasms; D008297:Male; D016296:Mutagenesis; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D034741:RNA, Small Interfering; D051381:Rats; D011924:Rats, Zucker; D014158:Transcription, Genetic / Q000502:physiology*
D002843:Chromatin; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D035941:Iron Regulatory Protein 1