Dual role of insulin in transcriptional regulation of the acute phase reactant ceruloplasmin.
Insulin is a potent negative regulator of the response of hepatic cells to pro-inflammatory cytokines, particularly, interleukin (IL)-6. The action of insulin is target-selective because it inhibits transcription of most but not all acute phase genes. We here show that ceruloplasmin ( Cp), an acute phase reactant with important functions in iron homeostasis, is subject to a unique dual regulation by insulin. IL-6 increased Cp mRNA expression in HepG2 cells by approximately 5-fold. Simultaneous treatment with insulin reduced this stimulation by half. Surprisingly, insulin by itself caused a 2-4-fold induction in Cp mRNA expression. The mechanism of induction by insulin was studied by transfecting into HepG2 cells chimeric constructs of the Cp 5'-flanking region driving luciferase. The activity of a 4800-bp segment of the Cp 5'-flanking region was increased 3-fold by insulin. Deletion and mutation analyses showed the requirement for a single hypoxia-responsive element in a 96-bp segment approximately 3600 bp upstream of the initiation site. The domains required for the two activities of insulin were distinct: The distal, hypoxia-responsive element-containing site was sufficient for Cp transactivation by insulin; in contrast, an 848-bp region adjacent to the initiation site was sufficient for IL-6 transactivation of Cp and for the inhibitory activity of insulin. The role of hypoxia-inducible factor-1 in the induction of Cp by insulin was shown by electrophoretic mobility shift assays and by the absence of insulin-stimulated Cp promoter activation in mouse Hepa c4 cells deficient in hypoxia-inducible factor-1 activity. Taken together these results show that insulin functions as a bidirectional, condition-dependent regulator of hepatic cell Cp expression. The unique regulation of Cp may reflect its dual roles in inflammation and iron homeostasis.[1]References
- Dual role of insulin in transcriptional regulation of the acute phase reactant ceruloplasmin. Seshadri, V., Fox, P.L., Mukhopadhyay, C.K. J. Biol. Chem. (2002) [Pubmed]
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