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Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver

Biological Trace Element Research volume 199, pages 267–277 (2021)Cite this article

Abstract

The liver is contributed to maintaining body iron homeostasis and controlling of body adaptation to fasting. Although previous studies implied a negative relationship between iron and ghrelin in both mice and humans, it remains to be explored whether fasting or ghrelin has a functional effect on iron homeostasis in the liver. In this study, we examined the roles of fasting and ghrelin in modulating the protein expression of Fpn1, transferrin receptor 1 (TfR1), and ferritin light chain (Ft-L), as well as the mRNA expression of ghrelin, hepcidin, ghrelin O-acyltransferase (GOAT), and growth hormone secretagogue receptor 1 alpha (GHSR1α) in mouse liver and cultured hepatocytes. Our in vivo results suggested that fasting significantly upregulated the mRNA expression of ghrelin, GOAT, and GHSR1α, as well as the protein levels of ghrelin, Fpn1, and Ft-L, but not TfR1, in mouse liver. Interestingly, mRNA expression of hepcidin did not change significantly after fasting. Meanwhile, in cultured hepatocytes, ghrelin significantly increased the protein expression of Fpn1 but not Ft-L and TfR1 and significantly enhanced ERK phosphorylation. Furthermore, the pretreatment of cultured hepatocytes with either a pERK inhibitor or a GHSR1α antagonist abolished the effects of ghrelin on Fpn1 expression and ERK phosphorylation. Our findings confirmed that fasting increases iron export in the liver by upregulating Fpn1 expression through the ghrelin/GHSR1α/MAPK signaling pathway.

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Data Availability

All original data are available upon request.

Abbreviations

Fpn1:

Ferroportin 1

TfR1:

Transferrin receptor 1

Ft-L:

Ferritin-L

GOAT:

Ghrelin O-acyltransferase

GHSR1α:

Growth hormone secretagogue receptor 1α

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular-regulated protein kinase

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Funding

This study was funded by the Natural Science Foundation of China (Grants 81873924, 81471257, and 31300973); the Open Cooperation Program from Key Laboratory of Extreme Environmental Medicine, Ministry of Education (KL2019GY011); the Natural Science Foundation of Jiangsu Province in China (Grant BK20161283); and also sponsored by the Nantong Science and Technology Project (MS12018030, MS12018048).

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Author notes

  1. Qianqian Luo, Jianan Hu and Guang Yang contributed equally to this work.

Affiliations

  1. Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China

    Qianqian Luo, Jianan Hu, Xiaoyu Yuan, Zhongping Chen, Dan Wang, Yapeng Lu, Li Zhu & Guohua Wang

  2. Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China

    Guang Yang

  3. Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, Hubei, China

    Guang Yang

Authors
  1. Qianqian Luo
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  2. Jianan Hu
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  3. Guang Yang
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  4. Xiaoyu Yuan
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  5. Zhongping Chen
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  6. Dan Wang
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  7. Yapeng Lu
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  8. Li Zhu
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  9. Guohua Wang
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Contributions

G.H.W. and L.Z. conceived, organized, and supervised the work; Q.Q.L., J.N.H., and G.Y. performed the experiments; X.Y.Y., Z.P.C., D.W., and Y.P.L. contributed to the analysis of data; Q.Q.L. and G.H.W. prepared, wrote, and revised the manuscript.

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Correspondence to Li Zhu or Guohua Wang.

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All animal handling procedures were conducted in accordance with guidelines approved by the Laboratory Animal Ethics Committee of Nantong University.

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Luo, Q., Hu, J., Yang, G. et al. Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver. Biol Trace Elem Res 199, 267–277 (2021). https://doi.org/10.1007/s12011-020-02114-x

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Keywords

  • Fasting
  • Ghrelin
  • Iron-related proteins
  • Ferroportin (Fpn1)
  • MAPK signaling pathway