Copper (Cu) is essential for innate immunity; however, how neutrophils regulate Cu homeostasis to support their functions remains unclear. We found that myeloid progenitors express abundant Cu-transporter ATP7B targeted to distinct vesicles and store Cu in vesicles. During neutrophil differentiation, ATP7B is downregulated, whereas ATP7A, LOXL2, and SLC31A2 are induced, suggesting a coordinated switch from Cu storage to utilization. As mature neutrophils exit the bone marrow, cellular Cu levels drop markedly, indicating Cu release during late maturation or egress. Myeloid-specific deletion of Atp7b in mice uncouples lineage commitment from functional maturation: Atp7b-deficient cells differentiate into neutrophils but fail to mature fully, showing more mitochondria, fewer lysosome-like structures, lower abundance of Cebp-ε and Ngal, reduced tubulin levels, and disrupted microtubules. Following lipopolysaccharide injection, Atp7b-deficient bone marrow releases fewer neutrophils into the bloodstream. Together, these findings reveal a previously unrecognized role of the Cu-transport network in neutrophil maturation and egress.

Iron accumulation and mitochondrial dysfunction in astroglia are reported in Parkinson’s disease (PD). Astroglia control iron availability in neurons in which dopamine (DA) synthesis is affected in PD. Despite their intimate relationship the role of DA in astroglial iron homeostasis is limited. Here we show that DA degrades iron storage protein ferritin in astroglial cells involving lysosomal proteolysis. Lysosomal ferritinophagy is mainly associated with macroautophagy; however, we revealed the involvement of chaperone-mediated autophagy (CMA) in DA-induced ferritin degradation. In CMA, cytosolic proteins containing a specific pentapeptide motif bind with HSC70 to be transported to lysosome mediated by LAMP2A. We identified the conserved pentapeptide motif in ferritin-H (Ft-H), mutations of which resulted loss of its interaction with HSC70. Pharmacological inhibitors of HSC70 or LAMP2/2A knockdown blocks DA-induced Ft-H degradation. DA also induces cytosolic cargo NCOA4 for ferritinophagy. We further reveal that DA promotes cathepsin B to lysis ferritin within the lysosome. Inhibitor of cathepsin B, knocking down of LAMP2, or HSC70 inhibitor attenuate DA-induced elevated mitochondrial iron level. Our results establish a direct role of DA on astroglial iron homeostasis and novel involvement of CMA in ferritin degradation in response to a biological stimulus. These results also may help in better understanding iron dyshomeostasis and mitochondrial dysfunction reported in PD.

Wilson disease (WD) is a potentially fatal metabolic disorder caused by the inactivation of the copper (Cu) transporter ATP7B, resulting in systemic Cu overload and fibroinflammatory liver disease. The molecular mechanism and effects of elevated Cu on cytoskeletal dynamics in liver fibrogenesis are not clear. Here, we tested the regulation of hepatic cytoskeleton and fibrogenesis with respect to Cu overload in WD. Atp7b−/− (knockout) mice with established liver disease, hepatocyte-specific Atp7b△Hep knockout mice without fibroinflammatory disease, and the age-and sex-matched controls were compared using Western blotting, real-time quantitative reverse transcription PCR (qRT-PCR), immunohistochemical (IHC) staining and transcriptomics (RNA-sequencing) analysis. In Atp7b−/− mice with developed liver disease, there is a significant increase in cytoskeletal protein expression with a reduction in α-tubulin acetylation. In these mice before the onset of liver pathology, no significant changes in cytoskeletal nor hepatic stellate cell activation are observed. As hepatic copper levels rise, an increase in cytoskeletal proteins with a decrease in acetylated-α-tubulin/α-tubulin ratio occurs. RNA-sequencing, qRT-PCR, and immunostaining confirm that the tubulin is upregulated at the transcriptional level and hepatocytes are the primary source of early tubulin increases before fibrosis. An increase in α-tubulin with a decrease in α-tubulin acetylation via Hdac6 and Sirt2 induction facilitates fibrosis as reflected by concomitant increases in desmin and α-SMA immunostaining in Atp7b−/− mice at 20 weeks. Moreover, strongly positive correlations between α-tubulin and α-tubulin deacetylase with the expression of liver fibrosis markers are observed in animal and human WD. Hepatocyte-specific Atp7b△Hep mice lack significant changes in tubulin as well as fibrosis despite hepatic steatosis. This study provides evidence that microtubule destabilization causes cytoskeletal rearrangement and facilitates hepatic stellate cell (HSC) activation and fibrosis in the murine model of WD.

Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or beta-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in beta-thalassemia. Compared with Tfrcfl/fl;Alb-Cre- controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre- controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+and Tfrcfl/fl;Alb-Cre- mice, ablation of hepatocyte Tfrc in a mouse model of beta-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine beta-thalassemia.

α-lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuel production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mitochondria impairment. Treatment with LA corrected the morphology of Atp7a-/- cells similar to the Cu chelator bathocuproinedisulfonate (BCS) and improved mitochondria function; however, the mechanisms of LA and BCS action were different. Unlike BCS, LA did not decrease intracellular Cu but instead increased selenium levels that were low in Atp7a-/- cells. Proteome analysis confirmed distinct cell responses to these compounds and identified upregulation of selenoproteins as the major effect of LA on preadipocytes. Upregulation of selenoproteins was associated with an improved GSH:GSSG ratio in cellular compartments, which was lowered by elevated Cu, and reversal of protein oxidation. Thus, LA diminishes toxic effects of elevated Cu by improving cellular redox environment. We also show that selenium levels are decreased in tissues of a Wilson disease animal model, especially in the liver, making LA an attractive candidate for supplemental treatment of this disease.

Wilson disease (WD) is a metabolic disorder caused by inactivation of the copper-transporting ATPase 2 (ATP7B) and copper (Cu) overload in tissues. Excess Cu causes oxidative stress and pathologic changes with poorly understood mechanistic connections. In Atp7b−/− mice with established liver disease, Cu overload activates the stress-sensitive transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2). Nrf2 targets, especially sulfotransferase 1e1 (Sult1e1), are strongly induced and cause elevation of sulfated sterols, whereas oxysterols are decreased. This sterol misbalance results in inhibition of the liver X receptor (LXR) and up-regulation of LXR targets associated with inflammatory responses. Pharmacological inhibition of Sult1e1 partially reverses oxysterol misbalance and LXR inhibition. Contribution of this pathway to advanced hepatic WD was demonstrated by treating mice with an LXR agonist. Treatment decreased inflammation by reducing expression of proinflammatory molecules, diminished fibrosis by down-regulating the noncanonical transforming growth factor–β signaling pathway, and improved liver morphology and function. Thus, the identified pathway is an important driver of WD.

Wilson disease (WD) is a potentially fatal genetic disorder with a broad spectrum of phenotypic presentations. Inactivation of the copper (Cu) transporter ATP7B and Cu overload in tissues, especially in the liver, are established causes of WD. However, neither specific ATP7B mutations nor hepatic Cu levels, alone, explain the diverse clinical presentations of WD. Recently, the new molecular details of WD progression and metabolic signatures of WD phenotypes began to emerge. Studies in WD patients and animal models revealed the contributions of non-parenchymal liver cells and extrahepatic tissues to the liver phenotype, and pointed to dysregulation of nuclear receptors (NR), epigenetic modifications, and mitochondria dysfunction as important hallmarks of WD pathogenesis. This review summarizes recent advances in the characterization of WD pathophysiology and discusses emerging targets for improving WD diagnosis and treatment.

Wilson disease (WND) is caused by inactivation of the copper transporter ATP7B and copper accumulation in tissues. WND presentations vary from liver steatosis to inflammation, fibrosis, and liver failure. Diets influence the liver phenotype in WND, but findings are inconsistent. To better understand the impact of excess calories on liver phenotype in WND, the study compared C57BL/6J Atp7b(-/-) and C57BL/6J mice fed for 12 weeks with Western diet or normal chow. Serum and liver metabolites, body fat content, liver histology, hepatic proteome, and copper content were analyzed. Wild-type and Atp7b(-/-) livers showed striking similarities in their responses to Western diet, most notably downregulation of cholesterol biosynthesis, altered nuclear receptor signaling, and changes in cytoskeleton. Western diet increased body fat content and induced liver steatosis in males and females regardless of genotype; however, the effects were less pronounced in Atp7b(-/-) mice compared with those in the wild type mice. Although hepatic copper remained elevated in Atp7b(-/-) mice, liver inflammation was reduced. The diet diminished signaling by Rho GTPases, integrin, IL8, and reversed changes in cell cycle machinery and cytoskeleton. Overall, high calories decreased inflammatory response in favor of steatosis without improving markers of cell viability. Similar changes of cellular pathways during steatosis development in wild-type and Atp7b(-/-) mice explain histologic overlap between WND and non-alcoholic fatty liver disease despite opposite copper changes in these disorders.

Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human disease. However, their phenotypes vary, and neither the common response to copper overload nor factors contributing to variability are well defined. Using metabolic, histologic, and proteome analyses in three Atp7b-deficient mouse strains, we show that global inactivation of Atp7b enhances and specifically modifies the hepatocyte response to Cu overload. The loss of Atp7b only in hepatocytes dysregulates lipid and nucleic acid metabolisms and increases the abundance of respiratory chain components and redox balancing enzymes. In global knockouts, independently of their background, the metabolism of lipid, nucleic acid, and amino acids is inhibited, respiratory chain components are down-regulated, inflammatory response and regulation of chromosomal replication are enhanced. Decrease in glucokinase and lathosterol oxidase and elevation of mucin-13 and S100A10 are observed in all Atp7b mutant strains and reflect the extent of liver injury. The magnitude of proteomic changes in Atp7b−/− animals inversely correlates with the metallothioneins levels rather than liver Cu content. These findings facilitate identification of WD-specific metabolic and proteomic changes for diagnostic and treatment.

Wilson disease is caused by autosomal-recessive mutations that affect the copper transporter ATP7B, resulting in accumulation of copper in liver, brain, and other organs. Accordingly, hepatic and neurologic manifestations are common presentations of this rare disease. Interestingly, these hepatic and neurologic presentations can vary widely between affected individuals: patients can present with mild hepatitis, cirrhosis, acute liver failure, profound depression, dysarthria, spasticity, involuntary movements, or combinations of signs and symptoms. Although ATP7B mutations define Wilson disease, they do not explain the phenotypic variations and diverse clinical presentations, and no firm correlations between genotype and phenotype exist. For this reason, environmental factors and epigenetic phenomena are thought to contribute to Wilson disease pathogenesis. Previous work from Valentina Medici’s group determined that aberrant DNA methylation and abnormal 1-carbon metabolism are present in patients and animal models of Wilson disease.1Mordaunt C.E. Kieffer D.A. Shibata N.M. Członkowska A. Litwin T. Weiss K.H. Zhu Y. Bowlus C.L. Sarkar S. Cooper S. Wan Y.Y. Ali M.R. LaSalle J.M. Medici V. Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers.Epigenetics Chromatin. 2019; 12: 10Crossref PubMed Scopus (16) Google Scholar In this issue of Cellular and Molecular Gastroenterology and Hepatology, Sarode et al2Sarode G.V. Neier K. Shibata N.M. Shen Y. Goncharov D.A. Goncharova E.A. Mazi T.A. Joshi N. Settles M.L. LaSalle J.M. Medici V. Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation.Cell Mol Gastroenterol Hepatol. 2021; 12: 1457-1477Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar advance the understanding of Wilson disease by examining the relationship between hepatic copper overload, histone acetylation, and gene expression in an animal model of Wilson disease (Jackson laboratory toxic milk mouse [tx-j]). The researchers found that protein levels of histone deacetylase 4 and 5 (HDAC4/5) are 5- to 10-fold lower in 12- and 24-week-old tx-j mice compared with control animals. In vitro, copper overload in HepG2 cells reduced HDAC5 levels, and copper reduction by isoproterenol restored HDAC5 expression in a dose dependent manner. Further experiments provide evidence that AMPK increases HDAC phosphorylation, targeting it for cytosolic degradation. Consistent with reduced HDAC4/5 levels, the authors observed dysregulation of histone acetylation: H3ac, H3K9ac, and H3K27ac levels were increased in livers of tx-j mice. Furthermore, supplementing the tx-j mouse diet with methyl donors (via choline) or copper chelation restored levels of HDAC4/5. Integrated analysis of H3K9ac and H3K27ac by ChIP-seq and gene expression by RNA-seq demonstrated altered epigenetic regulation and transcripts of genes involved in energy metabolism and liver regeneration. Peroxisome proliferator-activated receptors (PPARs) are key regulators of energy metabolism and were selected for further analysis. PPAR α and γ were increased in tx-j mice and a high-fat diet further increased PPAR expression. Analysis of downstream targets (fibrosis, antioxidants, fatty acid oxidation) indicated that HDAC5 regulates PPAR α and γ and their associated pathways in Wilson disease. Genome-wide analyses of patients with Wilson disease and in ATP7b-/- mice have revealed dysregulation of nuclear receptor signaling as an early and preferential consequence of copper toxicity. Pathway analysis and functional studies indicate that the PPAR, Liver X receptor (LXR),3Hamilton J.P. Koganti L. Muchenditisi A. Pendyala V.S. Huso D. Hankin J. Murphy R.C. Huster D. Merle U. Mangels C. Yang N. Potter J.J. Mezey E. Lutsenko S. Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B(-/-) (Wilson disease) mice.Hepatology. 2016; 63: 1824-1841Google Scholar and Farnesoid X receptor (FXR)4Wooton-Kee C.R. Robertson M. Zhou Y. Dong B. Sun Z. Kim K.H. Liu H. Xu Y. Putluri N. Saha P. Coarfa C. Moore D.D. Nuotio-Antar A.M. Metabolic dysregulation in the Atp7b -/- Wilson's disease mouse model.Proc Natl Acad Sci U S A. 2020; 117: 2076-2083Crossref PubMed Scopus (16) Google Scholar signaling pathways are abnormal in Wilson disease models, and activation of these pathways can correct hepatic disease. The findings in the paper presented by Sarode et al2Sarode G.V. Neier K. Shibata N.M. Shen Y. Goncharov D.A. Goncharova E.A. Mazi T.A. Joshi N. Settles M.L. LaSalle J.M. Medici V. Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation.Cell Mol Gastroenterol Hepatol. 2021; 12: 1457-1477Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar nicely synergize with prior work in this field that seeks to explain the metabolic and lipid dysregulation found in Wilson disease and ultimately may explain its phenotypic diversity. Although alcoholic and nonalcoholic steatohepatitis represent 2 of the most common forms of liver disease in the world, single gene disorders are useful to gain a broader understanding of hepatic pathogenesis. One of the most common pathologic findings in Wilson disease is steatohepatitis. This paper presents crucial information that may help understand the metabolic underpinnings of common liver diseases with similar hepatic presentations. Wilson Disease: Intersecting DNA Methylation and Histone Acetylation Regulation of Gene Expression in a Mouse Model of Hepatic Copper AccumulationCellular and Molecular Gastroenterology and HepatologyVol. 12Issue 4PreviewThe pathogenesis of Wilson disease (WD) involves hepatic and brain copper accumulation resulting from pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior methylome investigations in human WD liver and blood and in the Jackson Laboratory (Bar Harbor, ME) C3He-Atp7btx-j/J (tx-j) WD mouse model revealed an epigenetic signature of WD, including changes in histone deacetylase (HDAC) 5. We tested the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD. Full-Text PDF Open Access

BACKGROUND AND AIMS:Bone morphogenetic proteins BMP2 and BMP6 play key roles in systemic iron homeostasis by regulating production of the iron hormone hepcidin. The homeostatic iron regulator (HFE) also regulates hepcidin through a mechanism that intersects with the BMP-mothers against decapentaplegic homolog 1/5/8 (SMAD1/5/8) pathway. However, the relative roles of BMP2 compared with BMP6 and whether HFE regulates hepcidin through a BMP2-dependent mechanism remain uncertain.APPROACH AND RESULTS:We therefore examined the iron phenotype of mice deficient for both Bmp2 and Bmp6 or both Bmp2 and Hfe compared with single knockout (KO) mice and littermate controls. Eight-week-old double endothelial Bmp6/Bmp2 KO mice exhibited a similar degree of hepcidin deficiency, serum iron overload, and tissue iron overload compared with single KO mice. Notably, dietary iron loading still induced liver SMAD5 phosphorylation and hepcidin in double Bmp6/endothelial Bmp2 KO mice, although no other BMP ligand mRNAs were increased in the livers of double KO mice, and only Bmp6 and Bmp2 mRNA were induced by dietary iron loading in wild-type mice. In contrast, double Hfe/endothelial Bmp2 KO mice exhibited reduced hepcidin and increased extrahepatic iron loading compared to single Hfe or endothelial Bmp2 KO mice. Liver phosphorylated SMAD5 and the SMAD1/5/8 target inhibitor of DNA binding 1 (Id1) mRNA were also reduced in double Hfe/endothelial Bmp2 KO compared with single endothelial Bmp2 KO female mice. Finally, hepcidin and Id1 mRNA induction by homodimeric BMP2, homodimeric BMP6, and heterodimeric BMP2/6 were blunted in Hfe KO primary hepatocytes.CONCLUSIONS:These data suggest that BMP2 and BMP6 work collaboratively to regulate hepcidin expression, that BMP2-independent and BMP6-independent SMAD1/5/8 signaling contributes a nonredundant role to hepcidin regulation by iron, and that HFE regulates hepcidin at least in part through a BMP2-independent but SMAD1/5/8-dependent mechanism.

A failure of iron to appropriately regulate liver hepcidin production is central to the pathogenesis of hereditary hemochromatosis. SMAD1/5 transcription factors, activated by bone morphogenetic protein (BMP) signaling, are major regulators of hepcidin production in response to iron; however, the role of SMAD8 and the contribution of SMADs to hepcidin production by other systemic cues remain uncertain. Here, we generated hepatocyte Smad8 single ( Smad8fl/fl;Alb‐Cre+ ), Smad1/5/8 triple ( Smad158;Alb‐Cre+ ), and littermate Smad1/5 double ( Smad15;Alb‐Cre+ ) knockout mice to investigate the role of SMAD8 in hepcidin and iron homeostasis regulation and liver injury. We found that Smad8;Alb‐Cre+ mice exhibited no iron phenotype, whereas Smad158;Alb‐Cre+ mice had greater iron overload than Smad15;Alb‐Cre+ mice. In contrast to the sexual dimorphism reported for wild‐type mice and other hemochromatosis models, hepcidin deficiency and extrahepatic iron loading were similarly severe in Smad15;Alb‐Cre+ and Smad158;Alb‐Cre+ female compared with male mice. Moreover, epidermal growth factor (EGF) failed to suppress hepcidin in Smad15;Alb‐Cre+ hepatocytes. Conversely, hepcidin was still increased by lipopolysaccharide in Smad158;Alb‐Cre+ mice, although lower basal hepcidin resulted in lower maximal hepcidin. Finally, unlike most mouse hemochromatosis models, Smad158;Alb‐Cre+ developed liver injury and fibrosis at 8 weeks. Liver injury and fibrosis were prevented in Smad158;Alb‐Cre+ mice by a low‐iron diet and were minimal in iron‐loaded Cre– mice. Conclusion : Hepatocyte Smad1/5/8 knockout mice are a model of hemochromatosis that encompasses liver injury and fibrosis seen in human disease. These mice reveal the redundant but critical role of SMAD8 in hepcidin and iron homeostasis regulation, establish a requirement for SMAD1/5/8 in hepcidin regulation by testosterone and EGF but not inflammation, and suggest a pathogenic role for both iron loading and SMAD1/5/8 deficiency in liver injury and fibrosis.

Copper misbalance has been linked to fat accumulation in animals and experimental systems; however, information about copper homeostasis in human obesity is limited. In this study, the copper status of obese individuals was evaluated by measuring their levels of copper and cuproproteins in serum, adipose and hepatic tissues. The analysis of serum trace elements showed significant positive and element-specific correlation between copper and BMI after controlling for gender, age, and ethnicity. Serum copper also positively correlated with leptin, insulin, and the leptin/BMI ratio. When compared to lean controls, obese patients had elevated circulating cuproproteins, such as semucarbazide-sensitive amine oxidase (SSAO) and ceruloplasmin, and higher SSAO activity and copper levels in visceral fat. Although hepatic steatosis reduces copper levels in the liver, obese patients with no or mild steatosis have higher copper content in the liver compared to lean controls. In conclusion, obese patients evaluated in this study had altered copper status. Strong positive correlations of copper levels with BMI and leptin suggest that copper and/or cuproproteins may be functionally linked to fat accumulation.

The bone morphogenetic protein (BMP)-SMAD signaling pathway is a key transcriptional regulator of hepcidin in response to tissue iron stores, serum iron, erythropoietic drive and inflammation to increase the iron supply when needed for erythropoiesis, but to prevent the toxicity of iron excess. Recently, BMP2 was reported to play a non-redundant role in hepcidin regulation in addition to BMP6. Here, we used a newly validated BMP2 ELISA assay and mice with a global or endothelial conditional knockout (CKO) of Bmp2 or Bmp6 to examine how BMP2 is regulated and functionally contributes to hepcidin regulation by its major stimuli. Erythropoietin (EPO) did not influence BMP2 expression in control mice, and still suppressed hepcidin in Bmp2 CKO mice. Lipopolysaccharide (LPS) reduced BMP2 expression in control mice, but still induced hepcidin in Bmp2 CKO mice. Chronic dietary iron loading that increased liver iron induced BMP2 expression, whereas acute oral iron gavage that increased serum iron without influencing liver iron did not impact BMP2. However, hepcidin was still induced by both iron loading methods in Bmp2 CKO mice, although the degree of hepcidin induction was blunted relative to control mice. Conversely, acute oral iron gavage failed to induce hepcidin in Bmp6 -/- or CKO mice. Thus, BMP2 has at least a partially redundant role in hepcidin regulation by serum iron, tissue iron, inflammation and erythropoietic drive. In contrast, BMP6 is absolutely required for hepcidin regulation by serum iron.

Iron is an essential element for numerous fundamental biologic processes, but excess iron is toxic. Abnormalities in systemic iron balance are common in patients with chronic kidney disease and iron administration is a mainstay of anemia management in many patients. This review provides an overview of the essential role of iron in biology, the regulation of systemic and cellular iron homeostasis, how imbalances in iron homeostasis contribute to disease, and the implications for chronic kidney disease patients.