Induction of arachidonate 12-lipoxygenase (Alox15) in intestine of iron-deficient rats correlates with the production of biologically active lipid mediators

2008 ◽  
Vol 294 (4) ◽  
pp. G948-G962 ◽  
Author(s):  
James F. Collins ◽  
Zihua Hu ◽  
P. N. Ranganathan ◽  
Dian Feng ◽  
Laura M. Garrick ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Iron Deficiency ◽  
Membrane Lipid ◽  
Lipid Mediators ◽  
Biologically Active ◽  
Lipid Homeostasis ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Iron Deficient ◽  
12 Lipoxygenase

To identify novel genes associated with iron metabolism, we performed gene chip studies in two models of iron deficiency: iron-deprived rats and rats deficient in the principal intestinal iron transporter, divalent metal transporter 1 (i.e., Belgrade rats). Affymetrix rat genome gene chips were utilized (RAE230) with cRNA samples derived from duodenum and jejunum of experimental and control animals. Computational analysis and statistical data reduction identified 29 candidate genes, which were induced in both models of iron deficiency. Gene ontology analysis showed enrichment for genes related to lipid homeostasis, and one gene related to this physiological process, a leukocyte type, arachidonate 12-lipoxygenase ( Alox15), was selected for further examination. TaqMan real-time PCR studies demonstrated strong induction of Alox15 throughout the small and large intestine, and in the liver of iron-deficient rats. Polyclonal antibodies were developed and utilized to demonstrate that proteins levels are significantly increased in the intestinal epithelium of iron-deprived rats. HPLC analysis revealed altered intestinal lipid metabolism indicative of Alox15 activity, which resulted in the production of biologically active lipid molecules (12-HETE, 13-HODE, and 13-HOTE). The overall effect is a perturbation of intestinal lipid homeostasis, which results in the production of lipids essentially absent in the intestine of control rats. We have thus provided mechanistic insight into the alteration in lipid metabolism that occurs during iron deficiency, in that induction of Alox15 mRNA expression may be the primary event. The resulting lipid mediators may be related to documented alterations in villus structure and cell proliferation rates in iron deficiency, or to structural alterations in membrane lipid composition.

Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats

2005 ◽  
Vol 288 (5) ◽  
pp. L887-L893 ◽  
Author(s):  
Elizabeth Heilig ◽  
Ramon Molina ◽  
Thomas Donaghey ◽  
Joseph D. Brain ◽  
Marianne Wessling-Resnick
Keyword(s):  
Iron Deficiency ◽  
Iron Absorption ◽  
Iron Status ◽  
Mrna Levels ◽  
Blood Clearance ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Pulmonary Uptake ◽  
Iron Deficient ◽  
Metal Absorption

High levels of airborne manganese can be neurotoxic, yet little is known about absorption of this metal via the lungs. Intestinal manganese uptake is upregulated by iron deficiency and is thought to be mediated by divalent metal transporter 1 (DMT1), an iron-regulated factor known to play a role in dietary iron absorption. To better characterize metal absorption from the lungs to the blood and test whether iron deficiency may modify this process, the pharmacokinetics of pulmonary manganese and iron absorption by control and iron-deficient rats were compared. Levels of DMT1 expression in the lungs were determined to explore potential changes induced by iron deficiency that might alter metal absorption. The pharmacokinetic curves for intratracheally instilled54Mn and59Fe were significantly different, suggesting that pulmonary uptake of the two metals involves different mechanisms. Intratracheally instilled iron-deficient rats had significantly higher blood54Mn levels, whereas blood59Fe levels were significantly reduced compared with controls. The same trend was observed when radioisotopes were delivered by intravenous injection, indicating that iron-deficient rats have altered blood clearance of manganese. In situ analysis revealed the presence of DMT1 transcripts in airway epithelium; however, mRNA levels did not change in iron deficiency. Although lung DMT1 levels and metal absorption did not appear to be influenced by iron deficiency, the differences in blood clearance of instilled manganese identified by this study support the idea that iron status can influence the potential toxicity of this metal.

scholarly journals Exploration of the copper-related compensatory response in the Belgrade rat model of genetic iron deficiency

2011 ◽  
Vol 301 (5) ◽  
pp. G877-G886 ◽  
Author(s):  
Lingli Jiang ◽  
Perungavur Ranganathan ◽  
Yan Lu ◽  
Changae Kim ◽  
James F. Collins
Keyword(s):  
Iron Deficiency ◽  
Rat Model ◽  
Serum Copper ◽  
Compensatory Response ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Hepatic Copper ◽  
Metal Transporter ◽  
Liver Copper ◽  
Iron Deficient

The Menkes copper ATPase (Atp7a) and metallothionein (Mt1a) are induced in the duodenum of iron-deficient rats, and serum and hepatic copper levels increase. Induction of a multi-copper ferroxidase (ceruloplasmin; Cp) has also been documented. These findings hint at an important role for Cu during iron deficiency. The intestinal divalent metal transporter 1 (Dmt1) is also induced during iron deficiency. The hypothesis that Dmt1 is involved in the copper-related compensatory response during iron deficiency was tested, utilizing a mutant Dmt1 rat model, namely the Belgrade ( b/ b) rat. Data from b/ b rats were compared with phenotypically normal, heterozygous +/ b rats. Intestinal Atp7a and Dmt1 expression was increased in b/ b rats, whereas Mt1a expression was unchanged. Serum and liver copper levels did not increase in the Belgrades nor did Cp protein or activity. The lack of fully functional Dmt1 may thus partially blunt the compensatory response to iron deficiency by 1) decreasing copper levels in enterocytes, as exemplified by a lack of Mt1a induction and a lesser induction of Atp7a, 2) abolishing the frequently described increase in liver and serum copper, and 3) attenuating the documented increase in Cp expression and activity.

scholarly journals Increased DMT1 and FPN1 expression with enhanced iron absorption in ulcerative colitis human colon

2020 ◽  
Vol 318 (2) ◽  
pp. C263-C271 ◽  
Author(s):  
Emily A. Minor ◽  
Justin T. Kupec ◽  
Andrew J. Nickerson ◽  
Karthikeyan Narayanan ◽  
Vazhaikkurichi M. Rajendran
Keyword(s):  
Ulcerative Colitis ◽  
Iron Deficiency ◽  
Iron Absorption ◽  
Basolateral Membrane ◽  
Specific Inhibitor ◽  
Distal Colon ◽  
Human Colon ◽  
Deficiency Anemia ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter

Iron deficiency anemia is a common complication of ulcerative colitis (UC) that can profoundly impact quality of life. Most iron absorption occurs in the duodenum via divalent metal transporter 1 (DMT1)-mediated uptake and ferroportin-1 (FPN1)-mediated export across the apical and basolateral membranes, respectively. However, the colon also contains iron transporters and can participate in iron absorption. Studies have shown increased duodenal DMT1 and FPN1 in patients with UC, but there is conflicting evidence about whether expression is altered in UC colon. We hypothesized that expression of colonic DMT1 and FPN1 will also increase to compensate for iron deficiency. Quantitative RT-PCR and Western blot analyses were performed on duodenal and colonic segmental (right colon, transverse colon, left colon, and rectum) biopsies obtained during colonoscopy. DMT1 mRNA and protein abundances in colonic segments were approximately equal to those in the duodenum, whereas colonic FPN1 mRNA and protein abundances of colonic segments were about one-quarter of those of the duodenum. DMT1 specific mRNA and protein abundances were increased twofold, whereas FPN1 mRNA and protein expressions were increased fivefold in UC distal colon. Immunofluorescence studies revealed enhanced expression of apical membrane- and basolateral membrane-localized DMT1 and FPN1 in UC human colon, respectively. Increased DMT1 expression was associated with enhanced 2-(3-carbamimidoylsulfanylmethyl-benzyl)-isothiourea (CISMBI, DMT1 specific inhibitor)-sensitive 59Fe uptake in UC human colon. We conclude from these results that patients with active UC have increased expression of colonic iron transporters and increased iron absorption, which may be targeted in the treatment of UC-related anemia.

Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption

2002 ◽  
Vol 30 (4) ◽  
pp. 724-726 ◽  
Author(s):  
G.J. Anderson ◽  
D. M. Frazer ◽  
S.J. Wilkins ◽  
E. M. Becker ◽  
K. N. Millard ◽  
...  
Keyword(s):  
Iron Transport ◽  
Iron Absorption ◽  
Negative Regulator ◽  
Deficient Diet ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Hepcidin Expression ◽  
Iron Deficient ◽  
Transport Molecules

Hepcidin is an anti-microbial peptide predicted to be involved in the regulation of intestinal iron absorption. We have examined the relationship between the expression of hepcidin in the liver and the expression of the iron-transport molecules divalent-metal transporter 1, duodenal cytochrome b, hephaestin and Ireg1 in the duodenum of rats switched from an iron-replete to an iron-deficient diet or treated to induce an acute phase response. In each case, elevated hepcidin expression correlated with reduced iron absorption and depressed levels of iron-transport molecules. These data are consistent with hepcidin playing a role as a negative regulator of intestinal iron absorption.

scholarly journals Expression of Duodenal Iron Transporter Proteins in Diabetic Patients with and without Iron Deficiency Anemia

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Efrat Broide ◽  
Ram Reifen ◽  
Shay Matalon ◽  
Zipi Berkovich ◽  
Haim Shirin
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Transport ◽  
Deficiency Anemia ◽  
Diabetic Patients ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Transporter Proteins ◽  
Group A ◽  
Group B

The role of iron transport proteins in the pathogenesis of anemia in patients with diabetes mellitus (T2DM) is still unclear. We investigated the expression of duodenal transporter proteins in diabetic patients with and without iron deficiency anemia (IDA). Methods. Overall, 39 patients were included: 16 with T2DM and IDA (group A), 11 with T2DM without IDA (group B), and 12 controls (group C). Duodenal mucosal expression of divalent metal transporter 1 (DMT1), ferroportin 1 (FPN), hephaestin (HEPH), and transferrin receptor 1 (TfR) was evaluated by Western blotting. Chronic disease activity markers were measured as well. Results. FPN expression was increased in group A compared to group B and controls: 1.17 (0.72–1.46), 0.76 (0.53–1.04), and 0.71 (0.64–0.86), respectively (p=0.011). TfR levels were over expressed in groups A and B compared to controls: 0.39 (0.26–0.61), 0.36 (0.24–0.43), and 0.18 (0.16–0.24), respectively, (p=0.004). The three groups did not differ significantly with regard to cellular HEPH and DMT1 expression. The normal CRP and serum ferritin levels, accompanied with normal FPN among diabetic patients without IDA, do not support the association of IDA with chronic inflammatory state. Conclusion. In patients with T2DM and IDA, duodenal iron transport protein expression might be dependent on body iron stores rather than by chronic inflammation or diabetes per se.

Dietary iron-deficient anemia induces a variety of metabolic changes and even apoptosis in rat liver: a DNA microarray study

2010 ◽  
Vol 42 (2) ◽  
pp. 149-156 ◽  
Author(s):  
Asuka Kamei ◽  
Yuki Watanabe ◽  
Tomoko Ishijima ◽  
Mariko Uehara ◽  
Soichi Arai ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Iron Deficiency ◽  
Dna Microarray ◽  
Global Analysis ◽  
Control Diet ◽  
Diet Group ◽  
Iron Level ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Iron Deficient

Anemia can be induced by dietary iron deficiency, as well as by hemorrhagia. It may also be associated with changes in lipid metabolism. However, no global analysis detailing the consequences of iron deficiency in the liver has yet been conducted. Since the liver is a metabolically important organ and also a major iron-storing organ, we performed a comprehensive transcriptome analysis to determine the effects of iron deficiency on hepatic gene expression. Four-week-old rats were fed an iron-deficient diet, ∼3 ppm iron, ad libitum for 16 days. These rats were compared with similar rats pair-fed a control diet with a normal iron level, 48 ppm iron. The 16-day iron-deficient diet apparently induced anemia. On day 17, the rats were killed under anesthesia, and their livers were dissected for DNA microarray analysis. We identified 600 upregulated and 500 downregulated probe sets that characterized the iron-deficient diet group. In the upregulated probe sets, genes involved in cholesterol, amino acid, and glucose metabolism were significantly enriched, while genes related to lipid metabolism were significantly enriched in the downregulated probe sets. We also found that genes for caspases 3 and 12, which mediate endoplasmic reticulum (ER)-specific apoptosis, were upregulated in the iron-deficient group. Combined, these results suggest that iron deficiency exerts various influences, not only on nutrient metabolism but also on apoptosis, as a consequence of ER stress in the liver.

Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload

2001 ◽  
Vol 120 (6) ◽  
pp. 1412-1419 ◽  
Author(s):  
Heinz Zoller ◽  
Günter Weiss ◽  
Igor Theurl ◽  
Robert O. Koch ◽  
Wolfgang Vogel ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Ferroportin 1

scholarly journals Supplemental Microalgal Iron Helps Replete Blood Hemoglobin in Moderately Anemic Mice Fed a Rice-Based Diet

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2239
Author(s):  
Rohil S. Bhatnagar ◽  
Dennis D. Miller ◽  
Olga I. Padilla-Zakour ◽  
Xin Gen Lei
Keyword(s):  
Heme Iron ◽  
Deficiency Anemia ◽  
Free Access ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Minute Amount ◽  
Divalent Metal Transporter ◽  
Non Heme Iron ◽  
Blood Hemoglobin ◽  
Iron Deficient

Iron deficiency anemia affects 1.2 billion people globally. Our objectives were to determine if (1) supplemental iron extracted from defatted microalgae (Nannochloropsis oceanica, DGM) and (2) a combination of minute amount of plant phytase and inulin could help replete hemoglobin in anemic mice. Mice (7 weeks old) were fed a control diet (6 mg Fe/kg). After 10 weeks, the mice were assigned to three treatments: control, control + DGM iron (Fe-DGM, 39 mg Fe/kg), or control + 1% inulin + 250 units of phytase/kg (INU−PHY, 6 mg Fe/kg). The mice had free access to diets and water for 6 weeks. The Fe-DGM group had elevated blood hemoglobin (p < 0.01) and a two-fold greater (p < 0.0001) liver non-heme iron over the control. Strikingly, the INU-PHY group had 34% greater non-heme iron than the control, despite the same concentrations of iron in their diets. Fe-DGM group had altered (p < 0.05) mRNA levels of hepcidin, divalent metal transporter 1, transferrin and transferrin receptor 1. Iron extracted from defatted microalgae seemed to be effective in alleviating moderate anemia, and INU-PHY enhanced utilization of intrinsic iron present in the rice diet. Our findings may lead to a novel formulation of these ingredients to develop safer and bioavailable iron supplements for iron-deficient populations.

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