The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice

In conditions of increased erythropoiesis, expression of hepcidin, the master regulator of systemic iron homeostasis, is decreased to allow for the release of iron into the blood stream from duodenal enterocytes and macrophages. It has been suggested that hepcidin suppression is controlled by growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β superfamily of cytokines that is secreted from developing erythroblasts. In this study, we analyzed iron-related parameters in mice deficient for GDF15 under steady-state conditions and in response to increased erythropoietic activity induced by blood loss. We demonstrate that GDF15 suppresses the hepatic mRNA expression of some BMP/TGFβ target genes but not of hepcidin, and show that GDF15 is not required to balance iron homeostasis in response to blood loss.     

Impaired estrogen-induced uterine insulin-like growth factor-I gene expression in the streptozotocin diabetic rat

Summary Circulating somatomedin-C/insulin-like growth factor-I levels are low in the diabetic rat and unresponsive to exogenous growth hormone. However, the nature of this defect in growth hormone action remains unclear and there is little data on insulin-like growth factor-I gene expression in response to other stimuli and in non-hepatic tissues where insulin-like growth factor-I may have important paracrine and/or autocrine actions. We have previously shown that 17-beta estradiol stimulates uterine insulin-like growth factor-I expression in the ovariectomised rat. In this report uterine and hepatic insulin-like growth factor-I gene expression have been examined in the streptozotocin-diabetic rat. Serum insulin-like growth factor-I concentrations were significantly reduced in diabetic rats compared to normal rats (0.72±0.08 vs 1.23±0.05U/ml, p<0.0005) and hepatic insulin-like growth factor-I mRNA abundance was similarly reduced in diabetic rats to 49±5% of that seen in non-diabetic intact rats (p<0.005). In contrast, uterine insulin-like growth factor-I mRNA abundance was not significantly reduced in diabetic rats compared to control rats (76±12%, p = NS). Although both diabetic and non-diabetic rats demonstrated a significant increase in uterine wet weight following a single injection of 17-beta estradiol the increase in uterine insulinlike growth factor-I expression was significantly less marked in diabetic rats. Acute administration of insulin together with estradiol had no significant effect on serum insulin-like growth factor-I concentrations or hepatic insulin-like growth factor-I mRNA abundance; however, the uterine insulin-like growth factor-I response was significantly (p<0.01) augmented. The observations reported here demonstrate that hepatic insulin-like growth factor-I gene expression is markedly reduced in the diabetic rat and that the estradiol-induced uterine insulin-like growth factor-I response is significantly diminished, consistent with the hypothesis that there is a defect in insulin-like growth factor-I gene activation in the diabetic rat.     

Effects of iron regulatory protein regulation on iron homeostasis during hypoxia

Iron regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that affect the translation and stabilization of specific mRNAs by binding to stem-loop structures known as iron responsive elements (IREs). IREs are found in the 5'-untranslated region (UTR) of ferritin (Ft) and mitochondrial aconitase (m-Aco) mRNAs, and in the 3'-UTR of transferrin receptor (TfR) and divalent metal transporter-1 (DMT1) mRNAs. Our previous studies show that besides iron, IRPs are regulated by hypoxia. Here we describe the consequences of IRP regulation and show that iron homeostasis is regulated in 2 phases during hypoxia: an early phase where IRP1 RNA-binding activity decreases and iron uptake and Ft synthesis increase, and a late phase where IRP2 RNA-binding activity increases and iron uptake and Ft synthesis decrease. The increase in iron uptake is independent of DMT1 and TfR, suggesting an unknown transporter. Unlike Ft, m-Aco is not regulated during hypoxia. During the late phase of hypoxia, IRP2 RNA-binding activity increases, becoming the dominant regulator responsible for decreasing Ft synthesis. During reoxygenation (ReO2), Ft protein increases concomitant with a decrease in IRP2 RNA-binding activity. The data suggest that the differential regulation of IRPs during hypoxia may be important for cellular adaptation to low oxygen tension.     

Hepcidin和铁稳态

铁代谢紊乱引起的疾患是人类最常见的疾病。生理条件下，人体主要通过调控小肠铁吸收保持机体铁稳态。最近关于hepcidin的研究显示，这种肝脏合成的已知具有抗菌功能的多肽是控制小肠铁吸收，以及调节机体铁稳态的铁调节激素。肝脏hepcidin高表达可能是许多贫血包括炎症和慢性疾病性贫血的根本原因，而hepcidin表达障碍可能是许多铁过负荷类疾病的起因。     

Specificities in the synthesis of a cytoplasmic estrogen-induced uterine protein

The earliest known induction by estrogen of a specific uterine protein is that of the ‘induced protein’ (IP) of Gorski and colleagues, which is demonstrable within 40 min after treatment. We found that this protein is not restricted to the rat; it was detected in the uterus of prepuberal C3H/eB and SWR mice, l h after injection of 4 μg of estradiol-17β. IP was also induced in vivo by the non-steroidal plant estrogens genistein (1250 μg/rat) and coumestrol (300 μg/rat) and the synthetic estrogen diethylstilbestrol (5 μg/rat). We found no significant increase in the stimulation of the rate of IP synthesis by estrogen in uteri from either 10- or 20-day-old rats on subsequent treatment with actinomycin D, indicating that there was no superinduction of IP, despite a previous claim.     

Metabolic surgery and iron homeostasis

Iron deficiency and anaemia after metabolic surgery, potentially modifiable nutritional complications, are becoming an increasing cause for concern as prevalence increases with time and there is limited evidence supporting the effectiveness of the current guidelines for prophylactic oral iron supplementation and treatment for deficiency. Abnormalities in iron nutrition predisposing to deficiency are common in severely obese patients, and the low‐grade systemic inflammation, also common to these patients, reduces the effectiveness of oral iron supplementation. The surgical procedures result in alterations of foregut anatomy and physiology, which limit iron absorptive capacity and daily food intake. These alterations and the limited effects of oral iron supplementation explain the high prevalence of postoperative iron deficiency and anaemia. This review outlines current mechanisms concerning the pathogenesis of disordered iron nutrition in patients with severe obesity, current gaps in knowledge, and opportunities for quality improvement.     

Hereditary hemochromatosis: mutations in genes involved in iron homeostasis in Brazilian patients

Backgroundp.C282Y mutation and rare variants in the HFE gene have been associated with hereditary hemochromatosis (HH). HH is also caused by mutations in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y mutation in Brazil is suggestive that mutations in non-HFE genes may be linked to HH phenotype.AimTo screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population.Materials and methodsFifty-one patients with primary iron overload (transferrin saturation ≥ 50% in females and ≥ 60% in males) were selected. Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 exons was performed.ResultsThirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n = 11, 21.6%). In addition, heterozygous HFE p.S65C mutation was found in combination with p.H63D in two patients and homozygous HFE p.H63D was found in two patients as well. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms (p.A75V, p.A617A and p.R752H) and six SLC40A1 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704, rs11568346) and the novel mutation SLC40A1 p.G204S were also found.ConclusionsThe HFE p.C282Y in homozygosity or in heterozygosity with p.H63D was the most frequent mutation associated with HH in this sample. The HJV p.E302K and HAMP p.R59G variants, and the novel SLC40A1 p.G204S mutation may also be linked to primary iron overload but their role in the pathophysiology of HH remain to be elucidated.     

A genetic view of iron homeostasis

Inherited disorders of iron metabolism are invariably disorders of iron balance or distribution. This review describes the proteins known to be involved in establishing and maintaining iron balance, and discusses regulation of iron homeostasis in the context of three cell types: intestinal enterocytes, reticuloendothelial macrophages, and hepatocytes. It emphasizes information gleaned from the use of genetic analyses, particularly in mice, and poses new questions to help advance our understanding of iron balance.     

Cross-talk between iron homeostasis and intestinal inflammation

Recent publications from my laboratory have highlighted the important influence of altered iron homeostasis on the inflammatory response to intestinal bacteria. Here, I provide commentary on one of those papers, "Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice", which was published in the Journal of Clinical Investigation in October, 2009. It describes experiments that point to a previously unappreciated role for intracellular iron in the regulation of Toll-like receptor 4 signaling, and also demonstrates the potential therapeutic application of this information in a novel anti-inflammatory strategy based on manipulating iron balance. Our findings indicate that further investigation of the cross-talk between iron homeostasis and inflammation will yield new insights into the pathogenesis of chronic inflammatory diseases and may suggest new treatment approaches for these conditions.     

Cross-talk between iron homeostasis and intestinal inflammation

Recent publications from my laboratory have highlighted the important influence of altered iron homeostasis on the inflammatory response to intestinal bacteria. Here, I provide commentary on one of those papers, "Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice", which was published in the Journal of Clinical Investigation in November, 2009. It describes experiments that point to a previously unappreciated role for intracellular iron in the regulation of Toll-like receptor 4 signaling, and also demonstrates the potential therapeutic application of this information in a novel anti-inflammatory strategy based on manipulating iron balance. Our findings indicate that further investigation of the cross-talk between iron homeostasis and inflammation will yield new insights into the pathogenesis of chronic inflammatory diseases and may suggest new treatment approaches for these conditions.