2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Insulin-Like Growth Factor Binding Protein-1 Gene Expression and Counteracts the Negative Effect of Insulin

• Published in: Molecular pharmacology 2005-02, Vol.67 (2), p.444-452
• Main Authors: Marchand, A, Tomkiewicz, C, Marchandeau, J-P, Boitier, E, Barouki, R, Garlatti, M
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Down-Regulation - drug effects; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Insulin - pharmacology; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Proteins - antagonists & inhibitors; Insulin-Like Growth Factor Binding Proteins - biosynthesis; Insulin-Like Growth Factor Binding Proteins - genetics; Insulin-Like Growth Factor Binding Proteins - metabolism; Polychlorinated Dibenzodioxins - pharmacology; Pregnancy Proteins - antagonists & inhibitors; Pregnancy Proteins - biosynthesis; Pregnancy Proteins - genetics; Pregnancy Proteins - metabolism; Promoter Regions, Genetic - drug effects; Protein Binding; Receptors, Aryl Hydrocarbon - metabolism; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.104.004010

Recent epidemiological studies have revealed a possible correlation between exposure to high levels of dioxins or dioxin-like compounds and diabetes. Yet the interaction between insulin and dioxin actions remains elusive. We studied the regulation of insulin-like growth factor binding protein-1 (IGFBP-1), a protein involved in glucose homeostasis and whose expression is down-regulated by insulin. We showed that 2,3,7,8-tetrachorodibenzo- p -dioxin (TCDD) specifically induced IGFBP-1 mRNA in human hepatocytes and HepG2 human hepatoma cells (2.5- and 8-fold, respectively). Cellular and secreted IGFBP-1 protein levels were also up-regulated. Transfection and reporter assays showed that the IGFBP-1 promoter was activated by TCDD and that this activation was dependent on the integrity of a proximal xenobiotic-responsive element (XRE). This XRE, located near the insulin-glucocorticoid regulatory region, binds the aryl-hydrocarbon receptor. In agreement with previous studies, the IGFBP-1 promoter was down-regulated by insulin (50%); we show here that although TCDD activated the IGFBP-1 promoter 5- to 6-fold, the combination of TCDD and insulin led to an expression level of IGFBP-1 that was higher than basal level (2- to 3-fold activation). Similar regulations were observed for the endogenous IGFBP-1 mRNA. These data suggest that the xenobiotic-hormonal regulatory region of the IGFBP-1 promoter mediates an up-regulation of IGFBP-1 expression by TCDD even in the presence of insulin. Because IGFBP-1 modulates blood glucose levels, the up-regulation of IGFBP-1 by dioxins might account for the disruptive effects of these pollutants on glucose metabolism.