Viewpoint Cite This: Biochemistry XXXX, XXX, XXX-XXX
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Cross-Regulation of Iron and Glucose Metabolism in Response to Infection Ana Rita Carlos,† Sebastian Weis,‡ and Miguel P. Soares*,† †
Instituto Gulbenkian de Ciência, Oeiras, Portugal Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
‡
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infection, and sepsis,4 an often-lethal outcome of systemic bacterial infections. The mechanism(s) underlying the protective effect(s) of ferritin relies on the ferroxidase activity of FTH.3,4 Of note, FTH does not interfere directly with the pathogen load of the infected host,3,4 instead establishing disease tolerance to malaria3 and sepsis.4 Infection is associated with the development of anorexia, a hallmark of sickness behavior characterized by a reduction of food intake and the development of a metabolic response reducing blood glucose levels. While critical to establish disease tolerance to systemic bacterial infections,4,5 anorexia of infection must be tightly regulated such that blood glucose levels do not fall below a threshold that would otherwise compromise host survival.4 This level of control is enforced by ferritin, via a mechanism that sustains liver glucose production and prevents the development of lethal hypoglycemia in response to systemic bacterial infection.4 The requirement for a functional cross-talk between Fe and glucose metabolism in response to systemic infections relates primarily to the generation of labile heme, a pathologic byproduct of hemolysis (Figure 1).4 The Fe contained in the prosthetic heme groups of Hb is prone to oxidation, leading to oxidative modifications and eventually to destabilization of the globin chains of extracellular Hb, resulting in the release of heme. The resulting labile heme is pathogenic, via different mechanisms that include the repression of liver glucose-6phosphatase (G6Pase),4 an enzyme encoded by G6PC1, which catalyzes the removal of the phosphate group of glucose 6phosphate to produce glucose that can be exported into the circulation. The Fe contained in the protoporphyrin ring of heme represses liver G6Pase, and as such, Fe neutralization by ferritin promotes liver G6Pase expression.4 This is required to sustain liver glucose production and hence avoid the development of lethal hypoglycemia in response to systemic bacterial infections.4 Ferritin promotes G6PC1 transcription via a mechanism that remains to be established but is likely to involve the activation of one or several transcription factors regulating steady-state G6PC1 transcription4 (Figure 1). It is noteworthy that heme represses liver G6Pase via a mechanism involving toll-like receptor 4 (TLR4),4 suggesting that heme signals via this innate immune sensor to regulate liver glucose production4 (Figure 1). Whether ferritin interferes with TLR4 signaling to promote G6PC1 transcription has not been established. Regardless of whether the process is similar to that of mice, it remains to be determined whether regulation of liver G6Pase
ron (Fe) is the most abundant transition metal on earth, and perhaps for this reason, it was co-opted throughout evolution as a catalyst of redox-based reactions vital to support life, such as those involved in ATP production or the transport and storage of gaseous molecules.1 In mammals, the large majority of Fe is contained in the prosthetic heme groups of hemoproteins,1,2 the most abundant of which is hemoglobin (Hb), where Fe is used to transport oxygen inside red blood cells (RBC). Under physiological conditions, the Fe-heme contained in Hb is continuously recycled, upon the engulfment and digestion of senescent or damaged RBC by hemophagocytic macrophages.1,2 These express a constitutively high level of heme oxygenase 1 (HO-1), a heme-catabolizing enzyme that extracts Fe from heme and makes Fe available for cellular export via solute carrier family 40 member 1 (SLC40A1), also known as ferroportin 1 (FPN1).1,2 Once in plasma, Fe is tightly bound by transferrin and imported by RBC progenitors via transferrin receptor. The imported Fe is inserted into nascent protoporphyrins, by ferrochelatase, as the last step of heme synthesis, before incorporation into apo-Hb. Inflammatory responses are associated with systemic repression of cellular Fe export by SLC40A1, enforced by hepcidin, an acute phase peptide produced in the liver and secreted into the plasma in response to a variety of inflammatory agonists.1,2 This leads to the accumulation of Fe in hemophagocytic macrophages and parenchyma cells, disrupting Fe supply for heme synthesis in RBC progenitors, eventually leading to anemia. As it accumulates intracellularly, Fe can react with hydrogen peroxide (H2O2), via Fenton chemistry, generating hydroxyl radicals (HO•) and other reactive oxygen species (ROS) that are deleterious to cellular macromolecules and organelles.2 If not countered, Fe-driven oxidative stress can lead to cellular metabolic dysfunction and damage, as often associated with the pathogenesis of immunemediated inflammatory diseases. Presumably, this explains why mechanisms controlling intracellular Fe redox activity can impact the pathogenesis of a broad range of immune-mediated inflammatory diseases. Neutralization and storage of excess intracellular Fe are performed essentially by ferritin, a multimeric protein complex composed of adjustable ratios of ferritin heavy chain (FTH) and light chain (FTL), encoded by two distinct genes.2 The ferroxidase activity of FTH is critical for Fe neutralization, i.e., the conversion of Fe2+ into Fe3+, and each ferritin complex can store up to 4500 atoms of Fe3+. Previous work from our laboratory established that ferritin is essential to limit the pathogenic outcome of systemic infections in mice,2 as illustrated for malaria,3 the disease caused by Plasmodium © XXXX American Chemical Society
Received: July 28, 2017
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DOI: 10.1021/acs.biochem.7b00728 Biochemistry XXXX, XXX, XXX−XXX
Viewpoint
Biochemistry
Figure 1. Ferritin-mediated regulation of G6Pase. Bacterial toxins can trigger lysis of red blood cells (RBC) and release of hemoglobin (Hb) from RBC, generating labile heme. Signaling via TLR4, as triggered by bacterial toxins and/or by labile heme, represses liver glucose production, via a mechanism that involves the inhibition of G6PC1 transcription. Heme catabolism by HO-1 generates labile Fe that represses G6PC1 transcription, an effect countered via Fe storage by ferritin, which sustains G6PC1 transcription. As G6Pase accumulates in the endoplasmic reticulum (ER) of hepatocytes, it converts glucose 6-phospate into glucose, which is then released into circulation, maintaining blood glucose levels within a physiologic range compatible with host survival.
by ferritin is also required to sustain glucose metabolism in human sepsis. In support of this notion, there are wellestablished correlations between the severity of human sepsis and serum ferritin or glucose levels. This would suggest that the molecular mechanism(s) via which Fe-heme and ferritin regulate glucose metabolism might be targeted therapeutically to establish disease tolerance to human sepsis.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Miguel P. Soares: 0000-0002-9314-4833 Funding
Fundaçaõ para a Ciência e Tecnologia (HMSP-ICT/0018/ 2011 to M.P.S. and SFRH/BPD/101608/2014 to A.R.C.) and Deutsche Forschungsgemeinschaft (DFG; WE 4971/3 to S.W.). Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Muckenthaler, M. U., Rivella, S., Hentze, M. W., and Galy, B. (2017) A Red Carpet for Iron Metabolism. Cell 168, 344−361. (2) Gozzelino, R., and Soares, M. P. (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid. Redox Signaling 20, 1754− 1769. (3) Gozzelino, R., Andrade, B. B., Larsen, R., Luz, N. F., Vanoaica, L., Seixas, E., Coutinho, A., Cardoso, S., Rebelo, S., Poli, M., Barral-Netto, M., Darshan, D., Kuhn, L. C., and Soares, M. P. (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12, 693−704. (4) Weis, S., Carlos, A. R., Moita, M. R., Singh, S., Blankenhaus, B., Cardoso, S., Larsen, R., Rebelo, S., Schäuble, S., Del Barrio, L., Mithieux, G., Rajas, F., Lindig, S., Bauer, M., and Soares, M. P. (2017) Metabolic adaptation establishes disease tolerance to sepsis. Cell 169, 1263. (5) Wang, A., Huen, S. C., Luan, H. H., Yu, S., Zhang, C., Gallezot, J. D., Booth, C. J., and Medzhitov, R. (2016) Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation. Cell 166, 1512−1525.
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DOI: 10.1021/acs.biochem.7b00728 Biochemistry XXXX, XXX, XXX−XXX
