The Serine Protease Tmprss6 Regulates Hepcidin Expression, but Its Loss Does Not Cause Systemic Iron Deficiency In the Fetal and Neonatal Periods

Abstract Abstract 4258 Mutations in TMPRSS6 (matriptase-2), a transmembrane serine protease expressed by the liver, result in the clinical phenotype of iron refractory iron deficiency anemia (IRIDA). Additionally, common polymorphisms in TMPRSS6 have been associated with variation in laboratory parameters of iron homeostasis in healthy populations. TMPRSS6 increases iron absorption by reducing expression of the hepatic hormone, hepcidin, via down-regulation of a BMP/SMAD signaling cascade. Hepcidin promotes the internalization and degradation of the duodenal iron transporter, ferroportin, thereby inhibiting iron absorption. Previous studies have demonstrated that adult mice with Tmprss6 deficiency exhibit elevated hepatic hepcidin mRNA levels that are associated with decreased hepatic iron stores. In one study, genetic loss of Tmprss6 was shown to result in significant elevation of hepatic hepcidin expression in mice at birth; however, whether this hepcidin elevation was associated with abnormalities in iron homeostasis was not reported. We therefore asked if the elevated hepcidin levels present in newborn Tmprss6-/- pups correlate with abnormal parameters of iron homeostasis in the fetal or neonatal periods. To answer this question, we intercrossed Tmprss6+/− mice to generate Tmprss6+/+, Tmprss6+/−, and Tmprss6-/- progeny for phenotypic characterization at either gestational day 17.5 (E17.5) or postnatal day 0 (P0). Consistent with prior observations, Tmprss6-/- pups at P0 showed a 4.6-fold increase in hepatic hepcidin mRNA compared to Tmprss6+/+ littermates (p=.006). However, despite this elevation in hepcidin expression, Tmprss6-/- pups were not pale, and they showed no significant differences in body mass or hepatic non-heme iron concentration compared to Tmprss6+/+ and Tmprss6+/− littermates. At E17.5, Tmprss6-/- fetuses showed a 50-fold increase in hepatic hepcidin mRNA compared to Tmprss6+/+ littermates (p=.005). However, Tmprss6-/- fetuses also were not pale, and they showed no significant difference in body mass compared to Tmprss6+/+ and Tmprss6+/− littermates. Surprisingly, hepatic non-heme iron concentration at E17.5 was significantly higher in Tmprss6-/- fetuses than in Tmprss6+/+ fetuses (p=.003). To determine if the increased hepcidin expression of Tmprss6-/- fetuses might affect iron homeostasis in their pregnant mothers, we measured iron parameters in Tmprss6+/− females gestating E17.5 litters that were enriched for either Tmprss6+/+ or Tmprss6-/- fetuses. No significant effects of fetal genotype on maternal iron parameters were observed. In summary, our results demonstrate that Tmprss6 regulates hepcidin expression in the fetal and neonatal periods in mice. However, Tmprss6 deficiency does not appear to be associated with systemic iron deficiency at these stages of development, and fetal Tmprss6 expression does not have a significant effect on maternal iron homeostasis in late gestation. These results may have implications for understanding the maintenance of iron homeostasis in early development, and may provide insight into the evolution of IRIDA as well as other disorders of iron homeostasis. Disclosures: No relevant conflicts of interest to declare.

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Tmprss6, An Inhibitor of Hepatic Bmp/Smad Signaling, Is Required for Hepcidin Suppression and Iron Loading In a Mouse Model of β-Thalassemia

Blood ◽

10.1182/blood.v116.21.164.164 ◽

2010 ◽

Vol 116 (21) ◽

pp. 164-164

Author(s):

Karin E. Finberg ◽

Rebecca L. Whittlesey ◽

Stefano Rivella ◽

Nancy C. Andrews

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Heme Iron ◽

Mrna Levels ◽

Iron Loading ◽

Wild Type ◽

Smad Signaling ◽

Hepcidin Expression ◽

Non Heme Iron ◽

Hepcidin Mrna

Abstract Abstract 164 TMPRSS6, a transmembrane protease produced by the liver, is an essential regulator of mammalian iron homeostasis. TMPRSS6 inhibits the expression of hepcidin, a circulating peptide that decreases intestinal iron absorption and macrophage iron release, by down-regulating hepatic BMP/SMAD signaling for hepcidin production. Accordingly, TMPRSS6 mutations result in elevated hepcidin levels, impaired absorption of dietary iron, and systemic iron deficiency. Interestingly, in congenital iron loading anemias such as β-thalassemia, hepcidin levels are inappropriately low relative to body iron stores, a finding that has been postulated to result from the production of a hepcidin-repressing factor in the setting of ineffective erythropoiesis. Here we asked if Tmprss6 is required to achieve the hepcidin suppression present in Hbbth3/+ mice, a model of β-thalassemia intermedia. To test this, we bred Hbbth3/+ mice to mice harboring a targeted disruption of the Tmprss6 serine protease domain. We generated mice of various Hbb-Tmprss6 genotype combinations and compared parameters of systemic iron homeostasis at 8 weeks of age. Consistent with prior studies of Hbbth3/+ mice, Hbbth3/+ mice harboring 2 wild-type Tmprss6 alleles (Hbbth3/+Tmprss6+/+ mice) showed non-heme iron concentrations of liver, spleen, and kidney that were significantly elevated compared to wild-type controls. Homozygosity for Tmprss6 mutation, however, ameliorated the iron overload phenotype of Hbbth3/+ mice and led to systemic iron deficiency. Tissue non-heme iron concentrations were markedly reduced in Hbbth3/+Tmprss6−/− mice as compared to Hbbth3/+Tmprss6+/+ mice and were similar to levels observed in Tmprss6−/− mice harboring 2 wild-type Hbb alleles. Hbbth3/+Tmprss6−/− mice had hemoglobin levels similar to the thalassemic levels present in Hbbth3/+Tmprss6+/+ mice. However, compared to Hbbth3/+Tmprss6+/+ mice, Hbbth3/+Tmprss6−/− mice showed markedly reduced erythrocyte mean corpuscular volume and serum transferrin saturation, as well as increased red blood cell count. Interestingly, homozygous loss of Tmprss6 in Hbbth3/+ mice also led to marked reduction in splenomegaly and improvement in peripheral red blood cell morphology. Consistent with prior studies of Hbbth3/+ mice, Hbbth3/+Tmprss6+/+ mice displayed hepatic hepcidin mRNA levels that were similar to wild-type and were, therefore, inappropriately decreased relative to their increased hepatic iron stores. Hepatic mRNA levels of Bmp6, encoding a Bmp ligand that is transcriptionally regulated by iron and acts as a key regulator of hepcidin expression in vivo, were significantly elevated in Hbbth3/+Tmprss6+/+ mice, suggesting that their relative hepcidin deficiency does not result from impaired Bmp6 transcription. While Hbbth3/+Tmprss6+/+ mice showed suppressed hepcidin levels, homozygous loss of Tmprss6 alleviated their hepcidin suppression and led to elevated hepcidin mRNA levels similar to Tmprss6−/− mice harboring 2 wild-type Hbb alleles. Hbbth3/+Tmprss6−/− mice also showed elevated hepatic mRNA encoding Id1, another transcriptional target of Bmp/Smad signaling. These findings indicate that Tmprss6 is required to achieve the suppression of hepatic hepcidin expression that underlies systemic iron overload in Hbbth3/+ mice. Furthermore, our results demonstrate that, by up-regulating hepatic Bmp/Smad signaling for hepcidin production, genetic loss of Tmprss6 induces profound changes in systemic iron homeostasis in this thalassemia model. Disclosures: No relevant conflicts of interest to declare.

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Tmprss6 Is a Genetic Modifier of the Hfe-Hemochromatosis Phenotype in Mice.

Blood ◽

10.1182/blood.v114.22.625.625 ◽

2009 ◽

Vol 114 (22) ◽

pp. 625-625

Author(s):

Karin E. Finberg ◽

Rebecca Whittlesey ◽

Mark D. Fleming ◽

Nancy C. Andrews

Keyword(s):

Iron Deficiency ◽

Iron Content ◽

Serum Iron ◽

Iron Concentration ◽

Transferrin Saturation ◽

Heme Iron ◽

Deficiency Anemia ◽

Wild Type ◽

Non Heme Iron ◽

Serum Iron Concentration

Abstract Abstract 625 HFE-associated hereditary hemochromatosis is an autosomal recessive disorder characterized by inappropriately elevated absorption of dietary iron by the gastrointestinal mucosa, resulting in excessive storage of iron in multiple organs. A significant proportion of individuals who are homozygous for HFE mutations fail to develop clinical symptoms, suggesting that environmental and/or genetic factors may influence the penetrance of this disorder. In vitro and animal studies have revealed that HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that acts to inhibit iron absorption by the duodenum. In contrast, TMPRSS6, a transmembrane serine protease produced by the liver, acts to inhibit hepcidin expression; both humans and mice harboring TMPRSS6 mutations display impaired intestinal iron absorption, resulting in a phenotype of iron-refractory iron deficiency anemia (IRIDA). Here we asked if heterozygous or homozygous loss of Tmprss6 function could modify the iron overload phenotype of Hfe null (Hfe-/-) mice, a mouse model of human HFE-hemochromatosis. To test this, we bred Hfe-/- mice to Tmprss6-/- mice; the latter harbor a targeted disruption of the Tmprss6 serine protease domain and exhibit an IRIDA phenotype. We generated Hfe-/-Tmprss6+/+, Hfe-/-Tmprss6+/-, and Hfe-/-Tmprss6-/- female mice (6-10 mice per genotype), in which parameters of systemic iron homeostasis were compared at eight weeks of age by Student's t test. Consistent with previous study of Hfe-/- mice, Hfe-/- mice harboring two wild type Tmprss6 alleles (Hfe-/-Tmprss6+/+ mice) showed serum iron concentration, transferrin saturation, and hepatic non-heme iron content that were significantly elevated compared to wild type mice of similar genetic background. Heterozygosity for Tmprss6 mutation, however, markedly reduced the severity of the hemochromatosis phenotype of Hfe-/- mice. Compared to Hfe-/- mice with two wild type Tmprss6 alleles, Hfe-/- mice that were heterozygous for Tmprss6 mutation (Hfe-/-Tmprss6+/- mice) showed significant reductions in serum iron concentration (p<0.01), transferrin saturation (p<0.005), and non-heme iron content of liver (p<10-4). Furthermore, homozygosity for Tmprss6 mutation completely ameliorated the iron overload phenotype of Hfe-/- mice and in fact led to systemic iron deficiency. Compared to both Hfe-/-Tmprss6+/+ and Hfe-/-Tmprss6+/- mice, Hfe-/-Tmprss6-/- mice showed markedly reduced serum iron concentration (p<10-7), transferrin saturation (p<10-10), and non-heme iron content of liver (p<10-4). Hfe-/-Tmprss6-/- mice also displayed iron deficiency anemia and appeared phenotypically similar to previously characterized Tmprss6-/- mice harboring two wild type copies of Hfe. In summary, these results demonstrate that Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. These findings suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-hemochromatosis and raise the possibility that pharmacological inhibition of TMPRSS6 activity might prove an effective therapy in this disorder. Disclosures: No relevant conflicts of interest to declare.

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Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin

Blood ◽

10.1182/blood-2005-05-1845 ◽

2005 ◽

Vol 106 (8) ◽

pp. 2884-2889 ◽

Cited By ~ 180

Author(s):

Lan Lin ◽

Y. Paul Goldberg ◽

Tomas Ganz

Keyword(s):

Mrna Expression ◽

Iron Homeostasis ◽

Iron Concentration ◽

Protein Product ◽

Dependent Manner ◽

Hepcidin Expression ◽

Juvenile Hemochromatosis ◽

Repulsive Guidance Molecule ◽

Hepcidin Mrna

Abstract Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C, RgmC) are the major cause of juvenile hemochromatosis (JH). The protein product of HJV, hemojuvelin, contains a C-terminal glycosylphosphatidylinositol anchor, suggesting that it can be present in either a soluble or a cell-associated form. Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver. However, neither the specific role of hemojuvelin in maintaining iron homeostasis nor its relationship to hepcidin has been experimentally established. In this study we used hemojuvelin-specific siRNAs to vary hemojuvelin mRNA concentration and showed that cellular hemojuvelin positively regulated hepcidin mRNA expression, independently of the interleukin 6 pathway. We also showed that recombinant soluble hemojuvelin (rs-hemojuvelin) suppressed hepcidin mRNA expression in primary human hepatocytes in a log-linear dose-dependent manner, suggesting binding competition between soluble and cell-associated hemojuvelin. Soluble hemojuvelin was found in human sera at concentrations similar to those required to suppress hepcidin mRNA in vitro. In cells engineered to express hemojuvelin, soluble hemojuvelin release was progressively inhibited by increasing iron concentrations. We propose that soluble and cell-associated hemojuvelin reciprocally regulate hepcidin expression in response to changes in extracellular iron concentration. (Blood. 2005;106:2884-2889)

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NCOA4 is Regulated by HIF and Mediates Mobilization of Murine Hepatic Iron Stores After Blood Loss

Blood ◽

10.1182/blood.2020006321 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xiuqi Li ◽

Larisa Lozovatsky ◽

Abitha Sukumaran ◽

Luis Gonzalez ◽

Anisha Jain ◽

...

Keyword(s):

Blood Loss ◽

Iron Homeostasis ◽

Hepatoma Cell ◽

Iron Concentration ◽

Heme Iron ◽

Hepatic Iron ◽

Prolyl Hydroxylases ◽

Iron Stores ◽

Mrna Induction ◽

Non Heme Iron

The mechanisms by which phlebotomy promotes the mobilization of hepatic iron stores are not well understood. NCOA4 (nuclear receptor coactivator 4) is a widely-expressed intracellular protein previously shown to mediate the autophagic degradation of ferritin. Here, we investigate a local requirement for NCOA4 in the regulation of hepatic iron stores and examine mechanisms of NCOA4 regulation. Hepatocyte-targeted Ncoa4 knockdown in non-phlebotomized mice had only modest effects on hepatic ferritin subunit levels and non-heme iron concentration. After phlebotomy, mice with hepatocyte-targeted Ncoa4 knockdown exhibited anemia and hypoferremia similar to control mice with intact Ncoa4 regulation, but showed a markedly impaired ability to lower hepatic ferritin subunit levels and hepatic non-heme iron concentration. This impaired hepatic response was observed even when dietary iron was limited. In both human and murine hepatoma cell lines, treatment with chemicals that stabilize hypoxia inducible factor (HIF), including desferrioxamine, cobalt chloride, and dimethyloxalylglycine, raised NCOA4 mRNA. This NCOA4 mRNA induction occurred within 3 hours, preceded a rise in NCOA4 protein, and was attenuated in the setting of dual HIF-1a and HIF-2a knockdown. In summary, we show for the first time that NCOA4 plays a local role in facilitating iron mobilization from the liver after blood loss and that HIF regulates NCOA4 expression in cells of hepatic origin. Because the prolyl hydroxylases that regulate HIF stability are oxygen and iron-dependent enzymes, our findings suggest a novel mechanism by which hypoxia and iron deficiency may modulate NCOA4 expression to impact iron homeostasis.

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Aging is associated with increased brain iron through brain-derived hepcidin expression

10.1101/2021.09.06.459092 ◽

2021 ◽

Author(s):

Hossein Ardehali ◽

Tatsuya Sato ◽

Jason Solomon Shapiro ◽

Hsiang-Chun Chang ◽

Richard A Miller

Keyword(s):

Heme Iron ◽

Iron Accumulation ◽

Biological Processes ◽

Brain Iron ◽

Cellular Compartment ◽

Hepcidin Expression ◽

Non Heme Iron ◽

Oxidative Effects ◽

The Brain ◽

Hepcidin Mrna

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrate that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, feroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

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Aging is associated with increased brain iron through cortex-derived hepcidin expression

eLife ◽

10.7554/elife.73456 ◽

2022 ◽

Vol 11 ◽

Author(s):

Tatsuya Sato ◽

Jason Solomon Shapiro ◽

Hsiang-Chun Chang ◽

Richard A Miller ◽

Hossein Ardehali

Keyword(s):

Heme Iron ◽

Iron Accumulation ◽

Brain Iron ◽

Cellular Compartment ◽

Hepcidin Expression ◽

Non Heme Iron ◽

Ferroportin 1 ◽

Oxidative Effects ◽

The Brain ◽

Hepcidin Mrna

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

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Maternal iron deficiency alters trophoblast differentiation and placental development in rat pregnancy

Endocrinology ◽

10.1210/endocr/bqab215 ◽

2021 ◽

Author(s):

Hannah Roberts ◽

Andrew G Woodman ◽

Kelly J Baines ◽

Mariyan J Jeyarajah ◽

Stephane L Bourque ◽

...

Keyword(s):

Iron Deficiency ◽

Fetal Growth ◽

Growth And Development ◽

Iron Homeostasis ◽

Junctional Zone ◽

Altered Expression ◽

Expression Of Genes ◽

Iron Deficient ◽

Increased Risk ◽

Maternal Iron

Abstract Iron deficiency occurs when iron demands chronically exceed intake, and is prevalent in pregnant women. Iron deficiency during pregnancy poses major risks for the baby, including fetal growth restriction and long-term health complications. The placenta serves as the interface between a pregnant mother and her baby, and ensures adequate nutrient provisions for the fetus. Thus, maternal iron deficiency may impact fetal growth and development by altering placental function. We used a rat model of diet-induced iron deficiency to investigate changes in placental growth and development. Pregnant Sprague-Dawley rats were fed either a low-iron or iron-replete diet starting two weeks before mating. Compared to controls, both maternal and fetal hemoglobin were reduced in dams fed low-iron diets. Iron deficiency decreased fetal liver and body weight, but not brain, heart or kidney weight. Placental weight was increased in iron deficiency, due primarily to expansion of the placental junctional zone. The stimulatory effect of iron deficiency on junctional zone development was recapitulated in vitro, as exposure of rat trophoblast stem cells to the iron chelator deferoxamine increased differentiation toward junctional zone trophoblast subtypes. Gene expression analysis revealed 464 transcripts changed at least 1.5-fold (P<0.05) in placentas from iron-deficient dams, including altered expression of genes associated with oxygen transport and lipoprotein metabolism. Expression of genes associated with iron homeostasis was unchanged despite differences in levels of their encoded proteins. Our findings reveal robust changes in placentation during maternal iron deficiency, which could contribute to the increased risk of fetal distress in these pregnancies.

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Hepcidin as a Prospective Individualized Biomarker for Individuals at Risk of Low Energy Availability

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.2019-0006 ◽

2019 ◽

Vol 29 (6) ◽

pp. 671-681 ◽

Cited By ~ 5

Author(s):

Claire E. Badenhorst ◽

Katherine E. Black ◽

Wendy J. O’Brien

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Dietary Intervention ◽

Low Energy ◽

Energy Availability ◽

Dietary Interventions ◽

Hepcidin Expression ◽

Ketogenic Diets ◽

Increased Risk ◽

Low Energy Availability

Hepcidin, a peptide hormone with an acknowledged evolutionary function in iron homeostasis, was discovered at the turn of the 21st century. Since then, the implications of increased hepcidin activity have been investigated as a potential advocate for the increased risk of iron deficiency in various health settings. Such implications are particularly relevant in the sporting community where peaks in hepcidin postexercise (∼3–6 hr) are suggested to reduce iron absorption and recycling, and contribute to the development of exercise-induced iron deficiency in athletes. Over the last decade, hepcidin research in sport has focused on acute and chronic hepcidin activity following single and repeated training blocks. This research has led to investigations examining possible methods to attenuate postexercise hepcidin expression through dietary interventions. The majority of macronutrient dietary interventions have focused on manipulating the carbohydrate content of the diet in an attempt to determine the health of athletes adopting the low-carbohydrate or ketogenic diets, a practice that is a growing trend among endurance athletes. During the process of these macronutrient dietary intervention studies, an observable coincidence of increased cumulative hepcidin activity to low energy availability has emerged. Therefore, this review aims to summarize the existing literature on nutritional interventions on hepcidin activity, thus, highlighting the link of hepcidin to energy availability, while also making a case for the use of hepcidin as an individualized biomarker for low energy availability in males and females.

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Effect of Oral Supplementation of Healthy Pregnant Sows with Sucrosomial Ferric Pyrophosphate on Maternal Iron Status and Hepatic Iron Stores in Newborn Piglets

Animals ◽

10.3390/ani10071113 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1113

Author(s):

Rafał Mazgaj ◽

Mateusz Szudzik ◽

Paweł Lipiński ◽

Aneta Jończy ◽

Ewa Smuda ◽

...

Keyword(s):

Animal Model ◽

Pregnancy Outcome ◽

Iron Supplementation ◽

Iron Status ◽

Heme Iron ◽

Oral Iron ◽

Ferric Pyrophosphate ◽

Non Heme Iron ◽

Nutritional Studies ◽

Maternal Iron

Background: The similarities between swine and humans in physiological and genomic patterns, as well as significant correlation in size and anatomy, make pigs an useful animal model in nutritional studies during pregnancy. In humans and pigs iron needs exponentially increase during the last trimester of pregnancy, mainly due to increased red blood cell mass. Insufficient iron supply during gestation may be responsible for the occurrence of maternal iron deficiency anemia and decreased iron status in neonates. On the other hand, preventive iron supplementation of non-anemic mothers may be of potential risk due to iron toxicity. Several different regimens of iron supplementation have been applied during pregnancy. The majority of oral iron supplementations routinely applied to pregnant sows provide inorganic, non-heme iron compounds, which exhibit low bioavailability and intestinal side effects. The aim of this study was to check, using pig as an animal model, the effect of sucrosomial ferric pyrophosphate (SFP), a new non-heme iron formulation on maternal and neonate iron and hematological status, placental transport and pregnancy outcome; Methods: Fifteen non-anemic pregnant sows were recruited to the experiment at day 80 of pregnancy and randomized into the non-supplemented group (control; n = 5) and two groups receiving oral iron supplementation—sows given sucrosomial ferric pyrophosphate, 60 mg Fe/day (SFP; n = 5) (SiderAL®, Pisa, Italy) and sows given ferrous sulfate 60 mg Fe/day (Gambit, Kutno, Poland) (FeSO4; n = 5) up to delivery (around day 117). Biological samples were collected from maternal and piglet blood, placenta and piglet tissues. In addition, data on pregnancy outcome were recorded.; Results: Results of our study show that both iron supplements do not alter neither systemic iron homeostasis in pregnant sows nor their hematological status at the end of pregnancy. Moreover, we did not detect any changes of iron content in the milk and colostrum of iron supplemented sows in comparison to controls. Neonatal iron status of piglets from iron supplemented sows was not improved compared with the progeny of control females. No statistically significant differences were found in average piglets weight and number of piglets per litter between animals from experimental groups. The placental expression of iron transporters varied depending on the iron supplement.

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Sensing Iron: Reciprocal Regulation of Hepcidin mRNA by Soluble and Cell-Associated Hemojuvelin.

Blood ◽

10.1182/blood.v106.11.512.512 ◽

2005 ◽

Vol 106 (11) ◽

pp. 512-512

Author(s):

Lan Lin ◽

Y. Paul Goldberg ◽

Tomas Ganz

Keyword(s):

Iron Homeostasis ◽

Genomic Sequence ◽

Hepatoma Cell ◽

Hepatoma Cell Line ◽

Mrna Levels ◽

Dependent Manner ◽

Human Hepatoma Cell ◽

Hepcidin Expression ◽

Juvenile Hemochromatosis ◽

Hepcidin Mrna

Abstract Human genetic studies identified HJV (also called HFE2) as the major cause for juvenile hemochromatosis (JH). Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver. We attempted to establish the specific roles of HJV in iron metabolism, especially its relationship with hepcidin. Translation of the genomic sequence indicated a C-terminal GPI anchor for the protein product of HJV, hemojuvelin. This suggested that hemojuvelin may have either a soluble or a cell-associated form. In human hepatoma cell line Hep3B, knockdown of cellular HJV by siRNA decreased hepcidin expression, independently of the IL-6 pathway. Intriguingly, the addition of recombinant soluble hemojuvelin (rs-hemojuvelin) also suppressed hepcidin expression in primary human hepatocytes, in a log-linear dose-dependent manner, suggesting competition between soluble and cell-associated forms of hemojuvelin. Soluble hemojuvelin was found in human sera at concentrations similar to those required to suppress hepcidin mRNA in vitro. In cells engineered to express hemojuvelin, soluble hemojuvelin release was progressively inhibited by increasing iron or holotransferrin concentrations. Our study suggests that soluble and cell-associated hemojuvelin reciprocally regulate hepcidin mRNA levels, and that hemojuvelin may serve as a molecular messenger for iron homeostasis. Even in hepatocytes stimulated with IL-6, we observed strong suppression of hepcidin mRNA by rs-hemojuvelin. If rs-hemojuvelin or its active fragments also suppress hepcidin production in vivo, they could be used to alleviate anemia of inflammation.

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