Decreased hepatic iron in response to alcohol may contribute to alcohol-induced suppression of hepcidin

AbstractHepatic Fe overload has often been reported in patients with advanced alcoholic liver disease. However, it is not known clearly whether it is the effect of alcohol that is responsible for such overload. To address this lacuna, a time-course study was carried out in mice in order to determine the effect of alcohol on Fe homoeostasis. Male Swiss albino mice were pair-fed Lieber–DeCarli alcohol diet (20 % of total energy provided as alcohol) for 2, 4, 8 or 12 weeks. Expression levels of duodenal and hepatic Fe-related proteins were determined by quantitative PCR and Western blotting, as were Fe levels and parameters of oxidative stress in the liver. Alcohol induced cytochrome P4502E1 and oxidative stress in the liver. Hepatic Fe levels and ferritin protein expression dropped to significantly lower levels after 12 weeks of alcohol feeding, with no significant effects at earlier time points. This was associated, at 12 weeks, with significantly decreased liver hepcidin expression and serum hepcidin levels. Protein expressions of duodenal ferroportin (at 8 and 12 weeks) and divalent metal transporter 1 (at 8 weeks) were increased. Serum Fe levels rose progressively to significantly higher levels at 12 weeks. Histopathological examination of the liver showed mild steatosis, but no stainable Fe in mice fed alcohol for up to 12 weeks. In summary, alcohol ingestion by mice in this study affected several Fe-related parameters, but produced no hepatic Fe accumulation. On the contrary, alcohol-induced decreases in hepatic Fe levels were seen and may contribute to alcohol-induced suppression of hepcidin.

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Effects of acute and chronic inflammation on proteins involved in duodenal iron absorption in mice: a time-course study

British Journal Of Nutrition ◽

10.1017/s0007114512000189 ◽

2012 ◽

Vol 108 (11) ◽

pp. 1994-2001 ◽

Cited By ~ 4

Author(s):

Abitha Sukumaran ◽

Joe Varghese ◽

Jesintha Tamilselvan ◽

Visalakshi Jeyaseelan ◽

Thenmozhi Mani ◽

...

Keyword(s):

Chronic Inflammation ◽

Time Course ◽

Molecular Mechanisms ◽

Early Time ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Expression Levels ◽

Hepcidin Expression ◽

Time Course Study ◽

Acute And Chronic Inflammation

In order to understand better the molecular mechanisms involved in the pathogenesis of anaemia of inflammation, we carried out a time-course study on the effects of turpentine-induced acute and chronic inflammation on duodenal proteins involved in Fe absorption in mice. Expression levels of these proteins and hepatic hepcidin and serum Fe levels were determined in inflamed mice. In acutely inflamed mice, significantly increased expression of ferritin was the earliest change observed, followed by decreased divalent metal transporter 1 expression in the duodenum and increased hepcidin expression in the liver. Ferroportin expression increased subsequently, despite high levels of hepcidin. Hypoferraemia, which developed at early time periods studied, was followed by increased serum Fe levels at later points. The present results thus show that acute inflammation induced several changes in the expression of proteins involved in duodenal Fe absorption, contributing to the development of hypoferraemia. Resolution of inflammation caused attenuation of many of these effects. Effects in chronically inflamed mice were less consistent. The present results also suggest that inflammation-induced increases in ferritin appeared to override the effects of hepcidin on the expression levels of ferroportin in enterocytes.

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Goat milk consumption modulates liver divalent metal transporter 1 (DMT1) expression and serum hepcidin during Fe repletion in Fe-deficiency anemia

Journal of Dairy Science ◽

10.3168/jds.2013-7250 ◽

2014 ◽

Vol 97 (1) ◽

pp. 147-154 ◽

Cited By ~ 7

Author(s):

J. Díaz-Castro ◽

M. Pulido ◽

M.J.M. Alférez ◽

J.J. Ochoa ◽

E. Rivas ◽

...

Keyword(s):

Goat Milk ◽

Divalent Metal ◽

Fe Deficiency ◽

Deficiency Anemia ◽

Milk Consumption ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Metal Transporter ◽

Serum Hepcidin

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Skeletal Lipocalin-2 Is Associated with Iron-Related Oxidative Stress in ob/ob Mice with Sarcopenia

Antioxidants ◽

10.3390/antiox10050758 ◽

2021 ◽

Vol 10 (5) ◽

pp. 758

Author(s):

Eun Bee Choi ◽

Jae Hun Jeong ◽

Hye Min Jang ◽

Yu Jeong Ahn ◽

Kyu Hyeon Kim ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Iron Homeostasis ◽

Skeletal Muscle Regeneration ◽

Lipocalin 2 ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Metal Transporter ◽

Candidate Target ◽

And Oxidative Stress

Obesity and insulin resistance accelerate aging-related sarcopenia, which is associated with iron load and oxidative stress. Lipocalin-2 (LCN2) is an iron-binding protein that has been associated with skeletal muscle regeneration, but details regarding its role in obese sarcopenia remain unclear. Here, we report that elevated LCN2 levels in skeletal muscle are linked to muscle atrophy-related inflammation and oxidative stress in leptin-deficient ob/ob mice. RNA sequencing analyses indicated the LCN2 gene expression is enhanced in skeletal muscle of ob/ob mice with sarcopenia. In addition to muscular iron accumulation in ob/ob mice, expressions of iron homeostasis-related divalent metal transporter 1, ferritin, and hepcidin proteins were increased in ob/ob mice compared to lean littermates, whereas expressions of transferrin receptor and ferroportin were reduced. Collectively, these findings demonstrate that LCN2 functions as a potent proinflammatory factor in skeletal muscle in response to obesity-related sarcopenia and is thus a therapeutic candidate target for sarcopenia treatment.

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Iron as the Key Modulator of Hepcidin Expression in Erythroid Antibody-Mediated Hypoplasia

BioMed Research International ◽

10.1155/2014/421304 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

J. C. Fernandes ◽

P. Garrido ◽

S. Ribeiro ◽

P. Rocha-Pereira ◽

E. Bronze-da-Rocha ◽

...

Keyword(s):

Serum Iron ◽

Rare Complication ◽

Therapeutic Strategies ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Hepcidin Expression ◽

Metal Transporter ◽

Human Erythropoietin ◽

Underlying Mechanisms ◽

The Impact

Erythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. DecreasedEPOexpression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.

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Lung injury after ozone exposure is iron dependent

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00534.2005 ◽

2007 ◽

Vol 292 (1) ◽

pp. L134-L143 ◽

Cited By ~ 29

Author(s):

Andrew J. Ghio ◽

Jennifer L. Turi ◽

Michael C. Madden ◽

Lisa A. Dailey ◽

Judy D. Richards ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Injury ◽

Iron Homeostasis ◽

Biological Effects ◽

Ozone Exposure ◽

Divalent Metal Transporter 1 ◽

Hek 293 ◽

Divalent Metal Transporter ◽

Metal Transporter ◽

Elevated Expression

We tested the hypothesis that oxidative stress and biological effect after ozone (O3) exposure are dependent on changes in iron homeostasis. After O3 exposure, healthy volunteers demonstrated increased lavage concentrations of iron, transferrin, lactoferrin, and ferritin. In normal rats, alterations of iron metabolism after O3 exposure were immediate and preceded the inflammatory influx. To test for participation of this disruption in iron homeostasis in lung injury following O3 inhalation, we exposed Belgrade rats, which are functionally deficient in divalent metal transporter 1 (DMT1) as a means of iron uptake, and controls to O3. Iron homeostasis was disrupted to a greater extent and the extent of injury was greater in Belgrade rats than in control rats. Nonheme iron and ferritin concentrations were higher in human bronchial epithelial (HBE) cells exposed to O3 than in HBE cells exposed to filtered air. Aldehyde generation and IL-8 release by the HBE cells was also elevated following O3 exposure. Human embryonic kidney (HEK 293) cells with elevated expression of a DMT1 construct were exposed to filtered air and O3. With exposure to O3, elevated DMT1 expression diminished oxidative stress (i.e., aldehyde generation) and IL-8 release. We conclude that iron participates critically in the oxidative stress and biological effects after O3 exposure.

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Antioxidant Effect of Propofol in Gliomas and Its Association With Divalent Metal Transporter 1

Frontiers in Oncology ◽

10.3389/fonc.2020.590931 ◽

2020 ◽

Vol 10 ◽

Author(s):

Chenyi Yang ◽

Zhengyuan Xia ◽

Tang Li ◽

Yimeng Chen ◽

Mingshu Zhao ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Ampa Receptor ◽

Glioma Cells ◽

Divalent Metal ◽

Oxygen Species ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Metal Transporter

BackgroundOxidative stress enhances tumor invasion and metastasis in brain cancer. The activation of divalent metal transporter 1 (DMT1), which is regulated by glutamate receptors, can result in the increase of oxidative stress and risk of cancer development. Propofol, an anesthetic with antioxidant capacity, has been shown to decrease oxidative stress in several different types of cancer. However, the underlying mechanism remains unclear. Therefore, the present study aimed to elucidate the mechanism underlying the suppression of oxidative stress in glioma cells by propofol. It was hypothesized that propofol may inhibit oxidative stress in gliomas via suppressing Ca2+-permeable α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) receptor (CPAR)-DMT1 signaling.MethodsMale Wistar rats with C6 gliomas, which were established by intracranial injection of C6 glioma cells, were either treated with propofol or not for 6 h before being sacrificed. The levels of AMPA receptor subunit GluR2 and DMT1 protein expression were assessed using western blotting. The association between CPARs and DMT1 was confirmed in vitro using the AMPA receptor activator (R, S)-AMPA. Glutathione and reactive oxygen species assay kits were used to evaluate tumor oxidative stress. The effect of propofol on glioma proliferation was evaluated by determining tumor weight, cell cycles and a growth curve.ResultsPropofol infusion at either 20 or 40 mg/kg-1/h-1 increased GluR2 levels and downregulated DMT1 expression as well as glutathione content markedly in the periphery compared with that in the glioma core. The in vitro results revealed that (R, S)-AMPA increased DMT1 expression and reactive oxygen species levels, which were partly reversed by propofol treatment.ConclusionPropofol regulated DMT1 expression by modulating CPARs, resulting in the inhibition of tumor oxidative stress and glioma growth. The present study provides evidence for optimizing the selection of anesthetic drugs in perioperative management and prognosis of patients with glioma.

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Propofol suppresses oxidative stress in gliomas through down-regulating divalent metal transporter 1

British Journal of Anaesthesia ◽

10.1016/j.bja.2018.10.018 ◽

2019 ◽

Vol 122 (3) ◽

pp. e40-e41

Author(s):

C.Y. Yang ◽

H.Y. Wang ◽

Z.Y. Xia ◽

T. Li ◽

Y.M. Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Divalent Metal ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Metal Transporter

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Divalent Metal Transporter 1 Knock-Down Modulates IL-1β Mediated Pancreatic Beta-Cell Pro-Apoptotic Signaling Pathways through the Autophagic Machinery

International Journal of Molecular Sciences ◽

10.3390/ijms22158013 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8013

Author(s):

Taewook Kang ◽

Honggang Huang ◽

Thomas Mandrup-Poulsen ◽

Martin R. Larsen

Keyword(s):

Cell Death ◽

Divalent Metal ◽

Β Cells ◽

Β Cell ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Knock Down ◽

Metal Transporter ◽

Cell Functions ◽

Protective Proteins

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing.

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