Fasting up-regulates ferroportin 1 expression via a Ghrelin/GHSR/MAPK signaling pathway.
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.
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, China.|Pharmacological Evaluation and Research Center, Shanghai Institute of PharmaceuticalIndustry, Shanghai, China.|Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong, China.
Qian-Qian
QQ
Luo
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, China.
Yu-Fu
YF
Zhou
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, China.
Mesona Yung-Jin
MY
Chen
Pharmacological Evaluation and Research Center, Shanghai Institute of PharmaceuticalIndustry, Shanghai, China.
Li
L
Liu
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, China.
Juan
J
Ma
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, China.
Meng-Wan
MW
Zhang
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, China.
Fa-Li
FL
Zhang
Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Ya
Y
Ke
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai, China.
Zhong-Ming
http://orcid.org/0000-0001-7851-0455
ZM
Qian
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism*; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000201:enzymology*; D015854:Up-Regulation; D000098742:Ferroportin
D000217:Acyltransferases; D001052:Apoferritins; D027682:Cation Transport Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D054439:Ghrelin; D006727:Hormone Antagonists; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D000098742:Ferroportin; C000592182:Ghsr protein, Mouse; C526983:Mboat4 protein, mouse
a GHSR1α/MAPK pathway; ferroportin 1 (Fpn1); ghrelin; iron metabolism proteins