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Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption. [ABSTRACT FROM AUTHOR]

Background & aimsMulticopper ferroxidases (MCFs) facilitate intestinal iron absorption and systemic iron recycling, likely by a mechanism involving the oxidization of Fe2+ from the iron exporter ferroportin 1 for delivery to the circulating Fe3+ carrier transferrin. Hephaestin (HEPH), the only MCF known to be expressed in enterocytes, aids in the basolateral transfer of dietary iron to the blood. Mice lacking HEPH in the whole body (Heph-/- ) or intestine alone (Hephint/int ) exhibit defects in dietary iron absorption but still survive and grow. Circulating ceruloplasmin (CP) is the only other known MCF likely to interact with enterocytes. Our aim was to assess the effects of combined deletion of HEPH and CP on intestinal iron absorption and homeostasis in mice.MethodsMice lacking both HEPH and CP (Heph-/-Cp-/- ) and mice with whole-body knockout of CP and intestine-specific deletion of HEPH (Hephint/intCp-/- ) were generated and phenotyped.ResultsHeph-/-Cp-/- mice were severely anemic and had low serum iron, but they exhibited marked iron loading in duodenal enterocytes, the liver, heart, pancreas, and other tissues. Hephint/intCp-/- mice were moderately anemic (similar to Cp-/- mice) but were iron loaded only in the duodenum and liver, as in Hephint/int and Cp-/- mice, respectively. Both double knockout models absorbed iron in radiolabeled intestinal iron absorption studies, but the iron was inappropriately distributed, with an abnormally high percentage retained in the liver.ConclusionsThese studies indicate that HEPH and CP, and likely MCFs in general, are not essential for intestinal iron absorption but are required for proper systemic iron distribution. They also point to important extra-intestinal roles for HEPH in maintaining whole-body iron homeostasis.

Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer's disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development. [ABSTRACT FROM AUTHOR]

Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer’s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development.

Abstract Background Macrophages that accumulate in atherosclerotic plaques contribute to progression of the lesions to more advanced and complex plaques. Although iron deposition was found in human atherosclerotic plaques, clinical and pre-clinical studies showed controversial results. Several epidemiological studies did not show the positive correlation between a systemic iron status and an incidence of cardiovascular diseases, suggesting that the iron involvement occurs locally, rather than systemically. Results To determine the direct in vivo effect of iron accumulation in macrophages on the progression of atherosclerosis, we generated Apoe −/− mice with a macrophage-specific ferroportin (Fpn1) deficiency (Apoe −/− Fpn1 LysM/LysM ). Fpn1 deficiency in macrophages dramatically accelerated the progression of atherosclerosis in mice. Pathophysiological evidence showed elevated levels of reactive oxygen species, aggravated systemic inflammation, and altered plaque-lipid composition. Moreover, Fpn1 deficiency in macrophages significantly inhibited the expression of ABC transporters (ABCA1 and ABCG1) by decreasing the expression of the transcription factor LXRα, which reduced cholesterol efflux and therefore promoted foam cell formation and enhanced plaque formation. Iron chelation relieved the symptoms moderately in vivo, but drastically ex vivo. Conclusions Macrophage iron content in plaques is a critical factor in progression of atherosclerosis. The interaction of iron and lipid metabolism takes place in macrophage-rich atherosclerotic plaques. And we also suggest that altering intracellular iron levels in macrophages by systemic iron chelation or dietary iron restriction may be a potential supplementary strategy to limit or even regress the progression of atherosclerosis.

Patients with alcoholic liver disease ( ALD) often display disturbed iron indices. Hepcidin, a key regulator of iron metabolism, has been shown to be down-regulated by alcohol in cell lines and animal models. This down-regulation led to increased duodenal iron transport and absorption in animals. In this study, we investigated gene expression of duodenal iron transport molecules and hepcidin in three groups of patients with ALD (with anaemia, with iron overload and without iron overload) and controls. Expression of DMT1, FPN1, DCYTB, HEPH, HFE and TFR1 was measured in duodenal biopsies by using real-time PCR and Western blot. Serum hepcidin levels were measured by using ELISA. Serum hepcidin was decreased in patients with ALD. At the m RNA level, expressions of DMT1, FPN1 and TFR1 genes were significantly increased in ALD. This pattern was even more pronounced in the subgroups of patients without iron overload and with anaemia. Protein expression of FPN1 paralleled the increase at the m RNA level in the group of patients with ALD. Serum ferritin was negatively correlated with DMT1 m RNA. The down-regulation of hepcidin expression leading to up-regulation of iron transporters expression in the duodenum seems to explain iron metabolism disturbances in ALD. Alcohol consumption very probably causes suppression of hepcidin expression in patients with ALD. [ABSTRACT FROM AUTHOR]

Abstract: The present study examined the hypothesis that the iron exporter ferroportin (FPN1/SLC40A1) can also mediate cellular export of the essential trace element manganese, using Xenopus laevis oocytes expressing human FPN1. When compared to oocytes expressing only the divalent metal transporter-1 (DMT1/NRAMP2), 54Mn accumulation was lower in oocytes also expressing FPN1. FPN1-expressing oocytes exported more 54Mn than control oocytes (26.6±0.6% versus 7.1±0.5%, respectively, over 4h at pH 7.4 when preloaded with approximately 16μM 54Mn); however, there was no difference in 54Mn uptake between control and FPN1-expressing oocytes. FPN1-mediated Mn export was concentration dependent and could be partially cis-inhibited by 100μM Fe, Co, and Ni, but not by Rb. In addition, Mn export ability was significantly reduced when the extracellular pH was reduced from 7.4 to 5.5, and when Na+ was substituted with K+ in the incubation media. These results indicate that Mn is a substrate for FPN1, and that this export process is inhibited by a low extracellular pH and by incubation in a high K+ medium, indicating the involvement of transmembrane ion gradients in FPN1-mediated transport. [Copyright &y& Elsevier]

Background: Studies conducted in human infants suggest developmental changes in the regulation of iron absorption; however, little is known about the molecular mechanisms regulating iron absorption during infancy. Two intestinal iron transporters, divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), were recently identified. Objective: The objective was to investigate at a molecular level the regulation of iron absorption during infancy in a rat pup mode l. We examined the developmental expression of DMT1 and FPN1 and the effects of iron supplementation on their expression and on iron absorption and utilization during infancy. Design: Rat pups were given daily oral doses of 0, 30, or 150 μg Fe from day 2 to day 20 after birth. On days 10 and 20 after birth, 59Fe absorption, tissue minerals, and intestinal DMT1, FPN1, and ferritin expression were examined. To assess developmental expression, DMT1 and FPN1 were examined in control rats from days 1 to 50 after birth. Results: Intestinal DMT1 and FPN1 were significantly affected by age; expression increased dramatically by day 40. On day 10, no significant effect of iron supplementation on DMT1 and FPN1 gene expression or on iron absorption was observed. By day 20, DMT1 and FPN1 expression and iron absorption had decreased significantly with iron supplementation. Conclusions: During early infancy, rat pups are unable to downregulate intestinal iron transporters or iron absorption in response to iron supplementation, whereas down-regulation occurs during late infancy. The current findings provide evidence of the developmental regulation of iron absorption, which emphasizes the need for caution when giving iron supplements to infants at an early age. [ABSTRACT FROM AUTHOR]

Iron overload is positively associated with diabetes risk. However, the role of iron in adipose tissue remains incompletely understood. Here, we report that transferrin-receptor-1-mediated iron uptake is differentially required for distinct subtypes of adipocytes. Notably, adipocyte-specific transferrin receptor 1 deficiency substantially protects mice from high-fat-diet-induced metabolic disorders. Mechanistically, low cellular iron levels have a positive impact on the health of the white adipose tissue and can restrict lipid absorption from the intestine through modulation of vesicular transport in enterocytes following high-fat diet feeding. Specific reduction of adipocyte iron by AAV-mediated overexpression of the iron exporter Ferroportin1 in adult mice effectively mimics these protective effects. In summary, our studies highlight an important role of adipocyte iron in the maintenance of systemic metabolism through an adipocyte-enterocyte axis, offering an additional level of control over caloric influx into the system after feeding by regulating intestinal lipid absorption. [Display omitted] • TFRC expression is differentially required for distinct subtypes of adipocytes • Lowering iron in adipocytes leads to healthier WAT • Adipocyte iron levels activate an adipose-gut crosstalk to regulate gut lipid absorption • Lowering iron in WAT protects mice from high-fat-diet-induced metabolic dysfunction Zhang and colleagues reveal an important role of adipocyte iron content in the maintenance of systemic metabolic homeostasis through an adipose-gut axis. They find that lowering iron in white adipose tissue substantially protects mice from high-fat-diet-induced metabolic dysfunction by restricting intestinal lipid absorption. [ABSTRACT FROM AUTHOR]

Type I interferons (IFNs-I) fulfil multiple protective functions during pathogenic infections, but they can also cause detrimental effects and enhance immunopathology. Here, we report that IFNs-I promote the dysregulation of iron homeostasis in macrophages during systemic infections with the intracellular pathogen Candida glabrata , leading to fungal survival and persistence. By engaging JAK1, IFNs-I disturb the balance of the transcriptional activator NRF2 and repressor BACH1 to induce downregulation of the key iron exporter Fpn1 in macrophages. This leads to enhanced iron accumulation in the phagolysosome and failure to restrict fungal access to iron pools. As a result, C. glabrata acquires iron via the Sit1/Ftr1 iron transporter system, facilitating fungal intracellular replication and immune evasion. Thus, IFNs-I are central regulators of iron homeostasis, which can impact infection, and restricting iron bioavailability may offer therapeutic strategies to combat invasive fungal infections. • IFN-I-dependent surveillance ofcandidiasis dysregulates host iron homeostasis • IFNs-I disturb iron metabolism in macrophages via the NRF2 control axis • IFN-I-triggered iron accumulation in phagosomes enhances pathogen fitness • Ablation of fungal iron uptake transporters abrogates fungal fitness in vivo During invasive infections, macrophages and fungal pathogens compete for essential nutrients such as iron. Riedelberger et al. show that IFN-I immune responses are detrimental during systemic Candida glabrata infections, owing to a dysregulated control of host iron homeostasis, which in turn promotes fungal fitness and immune evasion. [ABSTRACT FROM AUTHOR]

Lung cancer morbidity and mortality remain the leading causes of tumor-associated death worldwide. The discovery of early diagnostic and prognostic markers of lung cancer could significantly improve the survival rate and decrease the mortality rate. FPN1 is the only known mammalian iron exporter. However, the molecular and biological functions of FPN1 in lung cancer remain unclear. Here, FPN1 mRNA expression in lung cancer was estimated using the TCGA, Oncomine, TIMER, and UALCAN databases. The prognostic role of FPN1 was evaluated using Kaplan-Meier plotter and PrognoScan. Associations between FPN1 and immune infiltration in lung cancer were evaluated by the TIMER and CIBERSORT algorithms. FPN1 mRNA and protein expressions were significantly downregulated in lung cancer. Low FPN1 expression was strongly related to worse prognosis in patients with lung cancer. GO and KEGG analyses and GSEA suggested that FPN1 was remarkably related to iron homeostasis and immunity. Importantly, FPN1 was remarkably associated with the infiltrating abundance of multiple immune cells. Moreover, FPN1 displayed a strong correlation with various immune marker sets. We investigated the clinical application value of FPN1 and provided a basis for the sensitive diagnosis, prognostication and targeted therapy of lung cancer.

The nicotianamine-iron chelate [NA-Fe 2+ ], which is found in many plant-based foods, has been recently described as a new form of bioavailable iron in mice and chickens. How NA-Fe 2+ is assimilated from the diet, however, remains unclear. The current investigation by Murata et al. has identified the proton-coupled amino acid transporter 1 (PAT1) as the main mechanism by which NA-Fe 2+ is absorbed in the mammalian intestine. Discovery of this new form of dietary iron and elucidation of its pathway of intestinal absorption may lead to the development of improved iron supplementation approaches., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

Background: We studied the association between iron intake and polymorphisms in the iron transporter gene, SLC40A1, and the risk of tuberculosis. Methods: We compared iron intake, the frequency of SLC40A1 mutations, and interactions between these variables among 98 TB patients and 125 controls in Kwazulu-Natal, South Africa. Results: Four SLC40A1 SNPs were associated with an increased risk of tuberculosis and one with reduced risk. We also found a gene-environment interaction for four non-exonic SNPs and iron intake. Conclusions: This pilot study demonstrated an association between polymorphisms in SLC40A1 and tuberculosis and provided evidence for an interaction between dietary iron and SLC40A1., Organismic and Evolutionary Biology