2,3,7,8-Tetrachlorodibenzo-p-dioxin induces insulin-like growth factor binding protein-1 gene expression and counteracts the negative effect of insulin

Mol Pharmacol. 2005 Feb;67(2):444-52. doi: 10.1124/mol.104.004010. Epub 2004 Oct 20.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / biosynthesis
  • Receptors, Aryl Hydrocarbon / metabolism

Substances

  • IGFBP1 protein, human
  • Insulin
  • Insulin-Like Growth Factor Binding Protein 1
  • Insulin-Like Growth Factor Binding Proteins
  • Polychlorinated Dibenzodioxins
  • Pregnancy Proteins
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon