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PLoS One. 2009 Aug 12;4(8):e6618. doi: 10.1371/journal.pone.0006618.

ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity.

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1
Iron genes and the Immune System, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.

Abstract

Endoplasmic reticulum (ER) stress induces a complex network of pathways collectively termed the unfolded protein response (UPR). The clarification of these pathways has linked the UPR to the regulation of several physiological processes. However, its crosstalk with cellular iron metabolism remains unclear, which prompted us to examine whether an UPR affects the expression of relevant iron-related genes. For that purpose, the HepG2 cell line was used as model and the UPR was activated by dithiothreitol (DTT) and homocysteine (Hcys). Here, we report that hepcidin, a liver secreted hormone that shepherds iron homeostasis, exhibits a biphasic pattern of expression following UPR activation: its levels decreased in an early stage and increased with the maintenance of the stress response. Furthermore, we show that immediately after stressing the ER, the stress-inducible transcription factor CHOP depletes C/EBPalpha protein pool, which may in turn impact on the activation of hepcidin transcription. In the later period of the UPR, CHOP levels decreased progressively, enhancing C/EBPalpha-binding to the hepcidin promoter. In addition, analysis of ferroportin and ferritin H revealed that the transcript levels of these iron-genes are increased by the UPR signaling pathways. Taken together, our findings suggest that the UPR can have a broad impact on the maintenance of cellular iron homeostasis.

PMID:
19672300
PMCID:
PMC2719873
DOI:
10.1371/journal.pone.0006618
[Indexed for MEDLINE]
Free PMC Article
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