Fasting up‐regulates ferroportin 1 expression via a Ghrelin/GHSR/MAPK signaling pathway

• Published in: Journal of cellular physiology 2018-01, Vol.233 (1), p.30-37
• Main Authors: Luo, Qian‐Qian, Zhou, Yu‐Fu, Chen, Mesona Yung‐Jin, Liu, Li, Ma, Juan, Zhang, Meng‐Wan, Zhang, Fa‐Li, Ke, Ya, Qian, Zhong‐Ming
• Format: Article
• Language: English
• Subjects: a GHSR1α/MAPK pathway; Acyltransferase; Acyltransferases - genetics; Acyltransferases - metabolism; Anemia; Animals; Apoferritins - genetics; Apoferritins - metabolism; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cells, Cultured; Children; Cytosol; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Fasting; Fasting - metabolism; Ferritin; ferroportin 1 (Fpn1); Ghrelin; Ghrelin - genetics; Ghrelin - metabolism; Hepcidin; Hormone Antagonists - pharmacology; Iron; Iron deficiency; iron metabolism proteins; Macrophages; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - enzymology; Male; MAP kinase; Metabolism; Mice, Inbred C57BL; Nuclear transport; Nutrient deficiency; Phosphorylation; Pretreatment; Protein Kinase Inhibitors - pharmacology; Proteins; Receptors, Ghrelin - antagonists & inhibitors; Receptors, Ghrelin - genetics; Receptors, Ghrelin - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Signal Transduction; Spleen; Spleen - drug effects; Spleen - enzymology; Transferrin; Transferrins; Translocation; Up-Regulation
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.25931

The significant positive correlation between ghrelin and iron and hepcidin levels in the plasma of children with iron deficiency anemia prompted us to hypothesize that ghrelin may affect iron metabolism. Here, we investigated the effects of fasting or ghrelin on the expression of hepcidin, ferroportin 1 (Fpn1), transferrin receptor 1 (TfR1), ferritin light chain (Ft‐L) proteins, and ghrelin, and also hormone secretagogue receptor 1 alpha (GHSR1α) and ghrelin O‐acyltransferase (GOAT) mRNAs in the spleen and/or macrophage. We demonstrated that fasting induces a significant increase in the expression of ghrelin, GHSR1α, GOAT, and hepcidin mRNAs, as well as Ft‐L and Fpn1 but not TfR1 proteins in the spleens of mice in vivo. Similar to the effects of fasting on the spleen, ghrelin induced a significant increase in the expression of Ft‐L and Fpn1 but not TfR1 proteins in macrophages in vitro. In addition, ghrelin was found to induce a significant enhancement in phosphorylation of ERK as well as translocation of pERK from the cytosol to nuclei. Furthermore, the increased pERK and Fpn1 induced by ghrelin was demonstrated to be preventable by pre‐treatment with either GHSR1α antagonist or pERK inhibitor. Our findings support the hypothesis that fasting upregulates Fpn1 expression, probably via a ghrelin/GHSR/MAPK signaling pathway. Fasting increases the expression of ghrelin, GHSR1α, GOAT as well as Ft‐L and Fpn1 proteins in the spleens of mice in vivo. Ghrelin increases the expression of Ft‐L and Fpn1 proteins as well as phosphorylation of ERK in macrophages in vitro. Fasting upregulates Fpn1 expression probably via a ghrelin/GHSR/MAPK signaling pathway.