2,3,7,8-Tetrachlorodibenzo-p-dioxin induces insulin-like growth factor binding protein-1 gene expression and counteracts the negative effect of insulin.
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.
Marchand
A
A
INSERM UMRS-490, Centre Universitaire des Saints-Pères, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
Tomkiewicz
C
C
Marchandeau
J-P
JP
Boitier
E
E
Barouki
R
R
Garlatti
M
M
D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D018970:Insulin-Like Growth Factor Binding Protein 1; D018969:Insulin-Like Growth Factor Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
C032231:IGFBP1 protein, human; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018969:Insulin-Like Growth Factor Binding Proteins; D000072317:Polychlorinated Dibenzodioxins; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon