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Cellular citrate levels establish a regulatory link between energy metabolism and the hepatic iron hormone hepcidin

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Abstract

Expression of the hepatic peptide hormone hepcidin responds to iron levels via BMP/SMAD signaling, to inflammatory cues via JAK/STAT signaling, to the nutrient-sensing mTOR pathway, as well as to proliferative signals and gluconeogenesis. Here, we asked the question whether hepcidin expression is altered by metabolites generated by intermediary metabolism. To identify such metabolites, we took advantage of a comprehensive RNAi screen, which revealed effectors involved in citrate metabolism. We show that the inhibition of citrate-consuming enzymes increases hepcidin mRNA expression in primary murine hepatocytes. Consistently, citrate treatment of primary murine hepatocytes or intravenous injection of citrate in mice increases cellular citrate concentrations and hepcidin expression. We further demonstrate that the hepcidin response to citrate involves the SMAD signaling pathway. These results reveal links between iron homeostasis and energy metabolism that may help to explain why iron levels are frequently altered in metabolic disorders.

Key messages

• Elevated citrate levels increase hepcidin mRNA expression in primary hepatocytes.

• Citrate treatment in primary hepatocytes activates hepcidin expression.

• Intravenous injection of citrate in mice increases hepcidin mRNA levels.

• The hepcidin response to citrate involves the BMP/SMAD signaling pathway.

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Acknowledgments

M.U.M. acknowledges funding from the Deutsche Forschungsgemeinschaft (SFB1118) and the Dietmar Hopp Stiftung. The authors thank Klaus Schmitt from the EMBL Laboratory for Animal Resources for his support with the animal experiments.

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Authors and Affiliations

  1. Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

    Ana Rita da Silva, Joana Neves, Katarzyna Mleczko-Sanecka & Martina U. Muckenthaler

  2. Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany

    Ana Rita da Silva, Joana Neves, Katarzyna Mleczko-Sanecka, Matthias W. Hentze & Martina U. Muckenthaler

  3. European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany

    Ana Rita da Silva & Matthias W. Hentze

  4. Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal

    Joana Neves

  5. Metabolism Centre, University Hospital Heidelberg, Heidelberg, Germany

    Amol Tandon & Sven W. Sauer

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  1. Ana Rita da Silva
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  2. Joana Neves
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da Silva, A.R., Neves, J., Mleczko-Sanecka, K. et al. Cellular citrate levels establish a regulatory link between energy metabolism and the hepatic iron hormone hepcidin. J Mol Med 95, 851–860 (2017). https://doi.org/10.1007/s00109-017-1551-3

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