Nutritional Modulation of Hepcidin in the Treatment of Various Anemic States

Abstract

Twenty years after its discovery, hepcidin is still considered the main regulator of iron homeostasis in humans. The increase in hepcidin expression drastically blocks the flow of iron, which can come from one's diet, from iron stores, and from erythrophagocytosis. Many anemic conditions are caused by non-physiologic increases in hepcidin. The sequestration of iron in the intestine and in other tissues poses worrying premises in view of discoveries about the mechanisms of ferroptosis. The nutritional treatment of these anemic states cannot ignore the nutritional modulation of hepcidin, in addition to the bioavailability of iron. This work aims to describe and summarize the few findings about the role of hepcidin in anemic diseases and ferroptosis, as well as the modulation of hepcidin levels by diet and nutrients.

Keywords: anemia; ferroptosis; hepcidin; iron homeostasis.

Figure 1

Main mechanisms involved in the regulation of hepcidin release. Increased iron accumulation in the liver stimulates hepcidin expression through two mechanisms, which converge during the activation of the SMAD4 factor. SMAD4 is the last player of the BMP/SMAD pathway, activated both by the increase in cellular iron in endothelial cells, which releases BMP-2 and BMP-6, and by the formation of the HFE-TRF2 complex in hepatocytes, after binding to holotransferrin. Inflammation, with its cytokines, can increase expression of hepcidin through various transcription factors: TGF-β acts on SMAD4; IL-1β stimulates C/EBP δ; and IL-6 actives STAT3. Even mild or moderate hypoxia, with increased NOX4 activity, can increase hepcidin release by activating STAT3. Increase in NOX4 activity acts on reticular stress, which stimulates hepcidin synthesis with the activation of the CREBH factor. The same factor is also involved in the metabolic responses induced by fasting. Finally, other molecules such as ERFE, sirtuin-1, miR-NA-122 and PDGF-BB, inhibit the activation of these transcription factors to varying degrees, reducing the expression of hepcidin. BMP/SMAD, Bone morphogenetic protein/Small Mother Against Decapentaplegic; BMP-2, Bone morphogenetic protein 2; BMP-6, Bone morphogenetic protein 6; cAMP, Cyclic Adenosine Mono Phosphate; C/EBP δ, CCAAT Enhancer-binding protein δ; CREBH, Cyclic AMP-responsive element-binding protein H; ER, Endoplasmic Reticulum; ERFE, Erythroferrone; Fe, iron; HFE, Hereditary hemochromatosis protein; IL-1β, Interleukin 1 β; IL-6, Interleukin 6; JAK/STAT, Janus kinase/Signal Transducer and Activator of Transcription; miRNA-122, micro Ribonucleic Acid 122; NOX4, NADPH Oxidase 4; Nrf2, Nuclear factor erythroid 2-related factor 2; PDGF-BB, Platelet-derived growth factor-BB; PPARGC1A, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 α; SMAD4, Small Mother Against Decapentaplegic 4; STAT3, Signal Transducer and Activator of Transcription 3; TGF-β, Tumor growth factor β; TRF1, transferrin receptor 1; TRF2, transferrin receptor 2.

Figure 2

Link between hepcidin and ferroptosis. DMT1, Divalent metal transporter 1; NOX4, NADPH Oxidase 4.