Session: 102. Regulation of Iron Metabolism: Poster III
Hematology Disease Topics & Pathways:
Biological Processes, iron metabolism
We have generated a mouse model with heterozygous depletion of the ferroportin allele (Slc40a1wt/trp). These mice show normal haematological parameters, serum iron levels and transferrin saturation. However, the liver is iron deficient and expresses low levels of hepcidin. The phosphorylation of SMAD1/5/8 proteins is lower in Slc40a1wt/trp compared to wild type littermates, explaining the hepcidin phenotype. To further investigate the molecular mechanism underlying hepcidin downregulation mediated by hepatic iron deficiency, we established a protocol to isolate hepatocytes and LSECs from total mouse liver and analyzed expression of iron-related genes. BMP6 is downregulated in LSECs of Slc40a1wt/trp mice, explaining the diminished activity of the SMAD1/5/8 signaling pathway. We next examined intracellular iron levels in hepatocytes and LSECs by measuring ferritin (Ft) and transferrin receptor 1 expression (Tfr1), two genes whose expression is regulated via the IRE/IRP system according to intracellular iron stores. Hepatocytes have an iron-deficient molecular signature, with low levels of Ft and a high expression of Tfr1. Surprisingly in LSECs both Ft and Tfr1 are unchanged, suggesting that this cellular population has unaltered iron levels.
Taken together, our results show for the first time that decreased hepatic iron content is self-sufficient to cause a dramatic reduction in hepcidin expression and secretion. The hepcidin downregulation in the Slc40a1wt/trp mouse model is caused by a reduction in BMP6 levels that correlates with hepatocyte iron content. BMP6 modulation cannot be explained either by differences in circulating iron or by altered intracellular iron levels of LSECs, suggesting that BMP6 is not regulated by LSEC-mediated iron sensing. In our mouse model BMP6 seems to be linked with the intracellular iron content of hepatocytes. Therefore, we hypothesize that hepatocytes are the sensor of liver iron content which controls BMP6 expression in LSECs. RNAseq analysis on hepatocytes from Slc40a1wt/trp mice has been performed to identify underlying mechanisms.
Disclosures: Muckenthaler: Novartis: Research Funding.