RESUMEN
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.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ayuno/metabolismo , Ghrelina/metabolismo , Macrófagos Peritoneales/enzimología , Receptores de Ghrelina/metabolismo , Transducción de Señal , Bazo/enzimología , Aciltransferasas/genética , Aciltransferasas/metabolismo , Animales , Apoferritinas/genética , Apoferritinas/metabolismo , Proteínas de Transporte de Catión/genética , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Ghrelina/genética , Antagonistas de Hormonas/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Masculino , Proteínas de la Membrana , Ratones Endogámicos C57BL , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/genética , Bazo/efectos de los fármacos , Regulación hacia ArribaRESUMEN
To understand the potential mechanisms involved in the beneficial effects of aspirin (ASA) in mood disorders, Alzheimer's (AD) and Parkinson's disease (PD), we investigated the effects of ASA on the expression of iron transport proteins transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1), and iron storage protein ferritin light chain (Ft-L) in interleukin-6 (IL-6)-treated PC-12 cells. We demonstrated that IL-6 alone could induce a severe decline in Fpn1 expression and cell viability, and an increase in Ft-L protein, while ASA could markedly diminish the effects of IL-6 on these parameters. We also found that IL-6 significantly increased hepcidin expression and janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation, while ASA also observably suppressed these IL-6-induced effects. The data imply that ASA increases Fpn1 expression by inhibiting hepcidin expression via the IL-6/JAK/STAT3 pathway and show that the reduced content of Ft-L is due to the increased Fpn1 and subsequent iron release in the cells. The reduction of iron in neuronal cells by the increased expression of Fpn1 might be partly associated with the beneficial effects of ASA on mood disorders, AD and PD.