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Regulatory Connections Between Iron and Glucose Metabolism

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Regulatory Connections Between Iron and Glucose Metabolism International Journal of Molecular Sciences Review Regulatory Connections between Iron and Glucose Metabolism Carine Fillebeen 1, Nhat Hung Lam 2, Samantha Chow 2, Amy Botta 2, Gary Sweeney 2 and Kostas Pantopoulos 1,* 1 Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC H3Y 1P3, Canada; carine.fi[email protected] 2 Department of Biology, York University, Toronto, ON M3J 1P3, Canada; [email protected] (N.H.L.); [email protected] (S.C.); [email protected] (A.B.); [email protected] (G.S.) * Correspondence: [email protected]; Tel.: +1-514-340-8260 (ext. 25293) Received: 17 September 2020; Accepted: 16 October 2020; Published: 21 October 2020 Abstract: Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease. Keywords: hepcidin; ferroportin; insulin; adipokines; IRP1; IRP2 1. Iron and Energy Metabolism Iron is a transition metal with critical biological functions [1]. In mammals, most of body iron is present in hemoglobin of red blood cells and mediates oxygen transport. Significant amounts of iron are also present within myoglobin of skeletal muscle cells. Other cell types require smaller quantities of iron for utilization by several metalloproteins. These include metabolic enzymes and oxidoreductases, which catalyze electron transfer reactions. The activity of mitochondrial aconitase, an enzyme catalyzing conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle, depends on a 4Fe-4S cluster in its active site. Moreover, four out of five complexes in the mitochondrial electron transport chain contain hemoproteins (such as cytochromes) or iron–sulfur cluster proteins. Thus, iron is essential for cellular energy metabolism. Cell culture experiments showed that iron depletion inhibits not only mitochondrial aconitase, but also other enzymes of the TCA cycle such as citrate synthase, isocitrate dehydrogenase and succinate dehydrogenase [2]. This decreases formation of NADH and ATP, and also reduces oxygen consumption in the electron transport chain. To compensate for the inhibition in respiration, the iron-depleted cell increases glycolysis for ATP synthesis. On the other hand, excessive iron negatively affects mitochondrial function. Thus, dietary iron overload of mice decreases oxidative phosphorylation in liver mitochondria and also promotes mitochondrial disfunction due to oxidative stress [3]. This is consistent with the notion that while iron is an essential nutrient, it may also become a potent biohazard by promoting oxidative stress [4]. The Janus face of iron indicates that balanced iron metabolism is Int. J. Mol. Sci. 2020, 21, 7773; doi:10.3390/ijms21207773 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7773 2 of 18 imperative for health [5]. Mechanisms underlying regulation of systemic and cellular iron metabolism areInt. summarized J. Mol. Sci. 2020 below., 21, x FOR PEER REVIEW 2 of 18 2. Systemic2. Systemic Iron Iron Metabolism Metabolism DevelopingDeveloping erythroid erythroid cells cells in in thethe bonebone marrowmarrow and most of of cells cells in in other other tissues tissues acquire acquire iron iron fromfrom transferrin, transferrin, the the plasma plasma iron iron carrier carrier [6]. Transferrin[6]. Transferrin is predominantly is predominantly replenished replenished by iron by recycled iron fromrecycled tissue macrophages,from tissue macrophages, which phagocytize which iron-richphagocytize senescent iron-rich red bloodsenescent cells red and blood degrade cells heme and via HO-1degrade (heme heme oxygenase via HO-1 1). (heme Liberated oxygenase iron is1). then Liberated released iron to isthe then bloodstream released to the via bloodstream the iron exporter via ferroportinthe iron exporter for reutilization. ferroportin Intestinal for reutilization. enterocytes Inte absorbstinal enterocytes iron from dietary absorb sourcesiron from via dietary DMT1 sources (divalent metalvia DMT1 transporter (divalent 1), whichmetal transporter is expressed 1), on which the apicalis expressed site, and on the release apical it site, to plasma and release on the it to basolateral plasma siteon via the ferroportin. basolateral Luminal site via ironferroportin. is previously Luminal reduced iron is from previously Fe3+ to Fereduced2+ by ferrireductases,from Fe3+ to Fe such2+ by as DCYTBferrireductases, (duodenal such cytochrome as DCYTB B). Ferroportin,(duodenal cytochrome DMT1 and B). DCYTB Ferroportin, are transcriptionally DMT1 and DCYTB induced are in iron-deficienttranscriptionally enterocytes induced by in HIF2iron-deficientα (hypoxia enterocytes inducible by factor HIF2 2αα )(hypoxia to stimulate inducible iron factor absorption 2α) to [ 7]. Understimulate physiological iron absorption conditions, [7]. Under the contribution physiological of conditions, dietary iron the to contribution the transferrin-bound of dietary iron plasma to the iron pooltransferrin-bound is small and mostly plasma serves iron to pool compensate is small and for mo non-specificstly serves iron to compensate losses. for non-specific iron losses.Iron efflux from cells is critical for body iron homeostasis and is negatively controlled by hepcidin, a peptideIron hormone efflux from that inactivatescells is critical ferroportin for body in iron macrophages, homeostasis enterocytes and is negatively and other controlled target cells by [ 8] hepcidin, a peptide hormone that inactivates ferroportin in macrophages, enterocytes and other (Figure1). Circulating hepcidin is synthesized by hepatocytes in the liver; however, hepcidin is target cells [8] (Figure 1). Circulating hepcidin is synthesized by hepatocytes in the liver; however, also locally produced in other tissues and appears to have critical cell-autonomous functions [9–11]. hepcidin is also locally produced in other tissues and appears to have critical cell-autonomous The hepcidin-encoding HAMP gene is primarily induced in response to iron or inflammatory signals [8]. functions [9–11]. The hepcidin-encoding HAMP gene is primarily induced in response to iron or Hepcidin deficiency causes uncontrolled release of iron to plasma, gradual saturation of transferrin inflammatory signals [8]. Hepcidin deficiency causes uncontrolled release of iron to plasma, gradual andsaturation buildup of transferrin redox-active and non-transferrin-bound buildup of redox-active iron non-transferrin- (NTBI). Thisbound is taken iron up (NTBI). by hepatocytes This is taken and otherup tissueby hepatocytes parenchymal and cells other leading tissue to systemicparenchymal iron overloadcells leading (hemochromatosis) to systemic [iron12]. Conversely,overload sustained(hemochromatosis) inflammatory [12]. induction Conversely, of sustained hepcidin inflammatory contributes to induction the anemia of hepcidin of inflammation, contributes the to the most frequentanemia anemia of inflammation, among chronically the most frequent ill patients anemia [13]. among chronically ill patients [13]. FigureFigure 1. 1.Hormonal Hormonal regulation regulation ofof systemicsystemic ironiron tratraffiffic byby hepcidin. Hepcidin Hepcidin is issynthesized synthesized in in hepatocyteshepatocytes of of the the liver in in response response to hyperferremi to hyperferremiaa iron or iron secretion or secretion of bone ofmorphogenetic bone morphogenetic protein protein(BMP6) (BMP6) and BMP2 and BMP2from liver from sinusoidal liver sinusoidal endothelial endothelial cells; BMP6 cells; secretion BMP6 reflects secretion increased reflects body increased iron bodystores. iron It binds stores. to the It bindsiron exporter to the ferroportin iron exporter in target ferroportin cells (redin arrows) target such cells as (redtissue arrows) macrophages, such as tissuehepatocytes macrophages, and intestinal hepatocytes epithelial and intestinal cells and epithelialinhibits ferroportin-mediated cells and inhibits ferroportin-mediated iron efflux. Hepcidin iron efflbindingux. Hepcidin directly binding inhibits directly iron efflux inhibits from iron ferroportin efflux from and ferroportinalso promotes and ferroportin also promotes internalization ferroportin internalizationand degradation. and These degradation. responses These cause responsescellular iron cause retention cellular and ironreduce retention plasma andiron reducelevels. plasma iron levels. Iron intake triggers hepcidin induction in response to increased iron saturation of plasma transferrin and secretion of BMP6 (bone morphogenetic protein 6) from liver sinusoidal endothelial cells [14] (Figure 1). Endothelial cells also secrete BMP2, which is thought to control basal hepcidin expression. Binding of BMP6 or BMP2 to cell surface BMP receptors promotes
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