P038 Targeting the hepcidin-ferroportin axis with Nrf2 agonists to treat iron deficiency anaemia in Inflammatory Bowel Disease

Abstract

Abstract Background Anaemia of inflammation is a common extraintestinal manifestation of IBD, impacting patient quality of life and hospitalisation rates. High circulating levels of proinflammatory cytokines induce hepatic production of the iron-regulatory peptide hormone hepcidin. By binding to the iron exporter ferroportin, hepcidin induces its internalisation and degradation, restricting the bioavailability and absorption of iron. This study aimed to test the effect of dimethyl fumarate (DMF) and sulforaphane (SFN), known activators of the transcription factor Nrf2, on the hepcidin-ferroportin (hep-fer) axis. Methods HepG2 cells were cultivated under standard conditions and treated with DMF or SFN for 16h. For reporter gene assays, plasmids were transfected by lipofection; luciferase activity was measured luminometrically. Quantitative real-time PCR was performed to determine mRNA expression. Proteins were detected by Western blot or LC-MS/MS. For gene knockdown, HepG2 cells were transfected with targeting or nontargeting siRNA duplexes. Graph Pad Prism v.7.00 and IBM SPSS 25 were used for statistical analysis. Results Both DMF and SFN reduced basic hepcidin expression and counteracted cytokine-induced hepcidin expression at promoter, mRNA and protein levels in HepG2 cells, independent of Nrf2 activation. Furthermore, DMF caused upregulation of ferroportin and ferritin at mRNA level, dependent on induction of Nrf2 and its downstream target haem oxygenase-1 (HO-1). Conclusion The Nrf2 agonists DMF and SFN might ameliorate anaemia of inflammation by disrupting the hep-fer axis by Nrf2-dependent and -independent mechanisms, and may be a promising therapeutic option for anaemia of inflammation for patients with IBD.