Augmenter of liver regeneration (ALR) alters iron homeostasis regulating proteins by modifying the IL-6-STAT3-pathway

Abstract

Augmenter of liver injury (ALR), an anti-apoptotic, anti-oxidative and anti-inflammatory protein is widely expressed and known for its hepatotropic properties. Interleukin 6 (IL-6) is a pro-inflammatory cytokine and the main trigger of the acute-phase response (APR) following tissue damage, infection or inflammation. Both ALR and IL-6 have been described to play pivotal roles in the process of liver damage and its consecutive regeneration. The acute-phase-protein hepcidin is the principal regulator of systemic iron homeostasis, decreasing iron-uptake and lowering plasma iron concentration. Hepcidin mRNA expression is mainly activated by IL-6. Furthermore, iron accumulation and lower hepcidin expression was observed in alcohol-fed ALR-deficient mice. We have shown earlier, that ALR has a dual effect on IL-6-signaling/APR in hepatocytes dependent of its localization. Exogenous ALR (rALR) attenuates and endogenously ALR enhances IL-6-signaling. Therefore we analyzed the impact of ALR on proteins responsible for regulating iron homeostasis. HepG2 cells (wt and sfALR-overexpressing) cells were treated with either IL-6 or BMP6, w/o rALR, and proteins of iron metabolism were analyzed qRT-PCR and western blot. Treatment with rALR diminished IL-6 induced expression of TfR1 and Zip14 (both iron uptake) in wt and sfALR-HepG2. Furthermore, rALR decreased hepcidin upon IL-6 stimulation only in wt cells. IL-6 induced expression of iron exporter ferroportin (FPN1) is reduced by rALR in sfALR-HepG2 cells. Additionally, rALR modulating effects on BMP6 induced expression was seen in sfALR-HepG2 for FPN1 and TfR1. Application of rALR might ameliorate IL-6 induced iron overload regulation of iron homeostasis by reducing iron uptake and increasing iron export.