ER Stress-Inducible Factor CHOP Affects the Expression of Hepcidin by Modulating C/EBPalpha Activity

• Type: Article in International Scientific Journal
• Date: 2009

Authors

Susana Oliveira (Author) Other; Jorge P Pinto (Author) Other; Goncalo Picarote (Author) Other; Vera M Costa (Author) Other; Felix Carvalho (Author) FFUP; Maria Rangel (Author) ICBAS; Maria de Sousa (Author) Other; Sergio F de Almeida (Author) Other

Journal

Title: PLoS ONE

Vol. 4

Final page: e6618

ISSN: 1932-6203

Publisher: Public Library of Science

Indexing

ISI Web of Knowledge - 77 Citations

Scopus - 82 Citations

Other information

Authenticus ID: P-003-GSJ

DOI: 10.1371/journal.pone.0006618

Abstract (EN): 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/EBP alpha 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/EBP alpha-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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11