Effect of chronic ethanol administration on iron metabolism in the rat

This study shows that the ingestion of ethanol provokes alterations in iron metabolism which may lead to iron overload. Impaired release of reticuloendothelial iron was shown by a decrease of the maximum red blood cell utilization when radioactive iron was supplied as colloidal iron. An impairment in the erythropoietic activity of ethanol-treated animals was also observed, as can be seen from the reduced plasma iron turnover and red blood cell utilization within 24 h of iron administration. A rise in marrow transit time was also observed. In ethanol-treated rats there was an increase in the amount of iron retained both in the liver and the spleen. This was observed in both sexes and also in the offspring from ethanol-treated mothers.     

巨噬细胞铁代谢Hepcidin-Fpn1轴及其在动脉粥样硬化的作用

动脉粥样硬化(As)与铁代谢相关联,但斑块中聚集的铁是产生致病作用还是只是在As疾病发生发展过程中溶血等导致的一个单纯后果还存在争议。巨噬细胞在As斑块的形成和发展中发挥关键作用。本文总结巨噬细胞铁代谢与As的研究进展。首先介绍在巨噬细胞铁代谢中发挥重要作用的Hepcidin-Fpn1轴;接着从炎症、感染、斑块内出血3个方面介绍巨噬细胞铁代谢对As发生发展的影响;最后介绍与铁代谢相关的As治疗的新思路。     

间歇性低氧对大鼠白细胞介素-1水平的影响

目的探讨间歇性低氧对大鼠血浆中IL-1的影响。方法借助OSAS大鼠动物模型,模拟OSAS患者夜间反复发生的间歇性低氧的病理生理改变,观察大鼠血浆中IL-1水平的变化。结果 OSAS大鼠血浆中IL-1β水平较正常对照组显著增高。结论反复间歇性低氧可能通过促进IL-1的释放,炎症反应的发生。     

Localisation of proteins of iron metabolism in the human placenta and liver

Two anatomical sites that are important in human iron metabolism are the liver and placenta. Liver macrophages recycle iron from erythrocytes, and the placenta transfers iron from the mother to the fetus. The cellular distribution of proteins involved in iron transport in these two sites was studied. Transferrin receptor-1 (TfR1) and Ferroportin (FPN) expression was found on the placental syncytiotrophoblast (STB) and were polarised such that TfR1 was on the apical maternal-facing membrane and FPN was on the basal fetal-facing membrane, consistent with unidirectional iron transport from mother to fetus. Ferritin was strongly expressed in the stroma, suggesting that fetal tissue can store and accumulate iron. HFE was on some parts of the basal STB and, where present, HFE clearly colocalised with FPN but not TfR1. In the stroma, both HFE and FPN were present on CD68+ Hofbauer macrophage cells. In liver, the location of HFE is controversial. Using four mouse monoclonals and two polyclonal sera we showed that the pattern of HFE expression mirrored the distribution of CD68+ macrophage Kupffer cells. FPN was also most strongly expressed by CD68+ Kupffer cells. These findings contribute to understanding how iron is transported and stored in the human placenta and liver.     

Role of interleukin-6 in hypoxic regulation of intestinal iron absorption

The regulation of intestinal iron absorption is not fully understood. Hepcidin, a liver-produced peptide, has recently been identified as a negative regulator of iron absorption in various conditions associated with altered iron metabolism (e.g. inflammation, anaemia, hypoxia). It is not clear whether these perturbants share a common signalling pathway. In this study, the importance of the cytokine interleukin-6 (IL-6) was investigated in the hypoxic mouse model. Hypoxia was associated with increased levels of circulating IL-6, decreased liver hepcidin mRNA and increased iron absorption (especially MT). A significant positive correlation existed between the total iron uptake and IL-6 levels in circulation. IL-6 per se, though inducing hepcidin mRNA, failed to affect basal iron absorption. The adaptive response to absorption following the hypoxic exposure was, however, more prominent if mice had been treated concurrently with IL-6. This enhancement in absorption occurred even though hepcidin mRNA was not significantly changed. Similar prominent responses were seen with both human and mouse IL-6. Anti-IL-6 antiserum normalised iron absorption in mice exposed to hypoxia, because of a reduction in the MT. These data indicate that IL-6 can influence iron absorption (especially MT) during the hypoxic exposure, but via a mechanism independent of hepcidin.     

Microcytic anemia with iron malabsorption: An inherited disorder of iron metabolism

Two siblings were identified with severe hypoproliferative microcytic anemia and iron malabsorption, in the absence of any gastrointestinal disorder or blood loss. These children had severe microcytosis (MCV 48 fl, hemoglobin 7.5 g/dl) with decreased serum iron, elevated serum TIBC, and decreased serum ferritin, despite prolonged treatment with oral iron. An iron challenge study with an oral dose of 2 mg/kg elemental iron as ferrous sulfate documented iron malabsorption. After treatment with intravenous iron dextran, there was an absence of the expected reticulocytosis and only a partial correction of the hemoglobin, hematocrit, and microcytosis. The bone marrow was hypocellular with abnormal iron incorporation into erythroid precursor cells. This appears to be a rare form of inherited anemia characterized by iron malabsorption and disordered iron metabolism that only partially corrects after the administration of parenteral iron. These features resemble those found in the microcytic mouse (mk/mk), which also has severe microcytic anemia and iron malabsorption that partially responds to parenteral iron. © 1996 Wiley-Liss, Inc.     

IL-1RⅠ IL-1RⅡ IL-1RAcP在骨关节炎滑膜中的表达及其生物学意义

目的探讨白细胞介素-1受体(IL-1R)家族中的3个成员IL-1RⅠ、IL-1RⅡ和IL-1R协同蛋白(IL-1RAcP)在骨关节炎(OA)滑膜中的表达和生物学意义。方法采用免疫组织化学和反转录聚合酶链反应(RT-PCR)方法检测了不同病程的107例OA患者膝关节滑膜组织中三者的表达情况。结果免疫组织化学显示IL-1RⅠ和IL-1RAcP在OA滑膜中强阳性表达,IL-1RⅡ在OA滑膜中阳性表达,在对照组中均呈阴性或弱阳性表达。RT-PCR显示IL-1RⅠ、IL-1RⅡ、IL-1RAcP在Ⅰ度OA滑膜中的表达均显著高于正常滑膜(P＜0．05),且IL-1RⅠ的表达显著高于IL-1RⅡ(P＜0．05),而与IL-1RAcP的差异无统计学意义(P＞0．05)。但在Ⅱ度和Ⅲ度OA滑膜中,IL-1RⅠ、IL-1RAcP的表达与在正常滑膜中的表达差异无统计学意义(P＞0．05),IL-1RⅡ在Ⅲ度OA滑膜中的表达显著高于正常组(P＜0．05)。结论IL-1RⅠ、IL-1RⅡ、IL-1RAcP在OA的发病机制中起着重要的作用,尤以IL-1RⅠ和IL-1RAcP为主,但其表达只在OA早期短期增加,与OA病情的发展可能无关。     

Effects of alcohol consumption on iron metabolism

Background/objectives: Patients with alcohol abuse frequently suffer from malnutrition which may result in insufficient iron distribution and iron overload or deficiency. Iron metabolism can be described by a combination of biochemical soluble transferrin receptor, ferritin, C-reactive protein (CRP), and hematological parameters. Here, vitamin B12 and folic acid state were assessed. Results on iron metabolism in patients with alcohol dependence in comparison with social drinkers are presented. Materials/methods: Samples from 101 patients with dependent alcohol consumption were included. The control group comprised 115 social drinkers. Inclusion criteria for patients with chronic regular drinking/social drinkers were positive/negative score of the Alcohol Use Disorders Identification Test (AUDIT), and positive/negative score for alcohol abuse/dependence (DSM-IV criteria). Results: Absolute values for ferritin and sTfR are increased in patients with alcohol dependence with current consumption (ALC) compared with social drinkers. No major differences are observed in the ratio of sTfR/log ferritin in comparison with social drinkers. Hemoglobin concentrations correlated between the two groups. Mean corpuscular volume (MCV) was significantly increased in the ALC collective compared to social drinkers. Eighty patients of the alcohol-dependent group had sufficient iron repletion, 11 had iron overload, 6 are suspicious for functional iron deficiency, and 4 are suspicious for reduced iron supply. No vitamin B12/folate deficiencies are observed in alcohol-dependent patients. Conclusions and Scientific Significance: No major abnormalities of iron metabolism are seen in patients with chronic alcohol ingestion besides the well-known macrocytic anemia. Iron overload is relatively frequent and observed in 9% of cases. No differences in vitamin B12 and folate levels were found between individuals with alcohol dependence and social drinkers.     

铁、雌激素与骨代谢＂铁三角＂关系

雌激素对骨代谢的影响已基本明了,铁对骨代谢的影响已有很多报道.近来研究结果显示铁与雌激素紧密相关.在骨质疏松症研究领域,铁与骨代谢、铁与雌激素和骨代谢与雌激素形成了一个新颖的＂铁三角＂关系.本文对有关文献进行梳理,以期为揭示绝经后女性合并铁蓄积的骨质疏松症发生机制提供新的思路.     

Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin

Iron homeostasis is critical for cellular and organismal function and is tightly regulated to prevent toxicity or anemia due to iron excess or deficiency, respectively. However, subcellular regulatory mechanisms of iron remain largely unexplored. Here, we report that SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) in hepatocytes controls systemic iron homeostasis in a ceruloplasmin (CP)-dependent, and ER stress-independent, manner. Mice with hepatocyte-specific Sel1L deficiency exhibit altered basal iron homeostasis and are sensitized to iron deficiency while resistant to iron overload. Proteomics screening for a factor linking ERAD deficiency to altered iron homeostasis identifies CP, a key ferroxidase involved in systemic iron distribution by catalyzing iron oxidation and efflux from tissues. Indeed, CP is highly unstable and a bona fide substrate of SEL1L-HRD1 ERAD. In the absence of ERAD, CP protein accumulates in the ER and is shunted to refolding, leading to elevated secretion. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD is responsible for the degradation of a subset of disease-causing CP mutants, thereby attenuating their pathogenicity. Together, this study uncovers the role of SEL1L-HRD1 ERAD in systemic iron homeostasis and provides insights into protein misfolding-associated proteotoxicity.

Systemic iron metabolism is tightly regulated for cellular and organismal function. Iron is stored in the hepatocytes and distributed to the peripheral tissues through an intricate process: Ferrous iron (Fe²⁺) is exported from hepatocytes via the iron exporter ferroportin (FPN1) and subsequently oxidized at the plasma membrane by a ferroxidase known as ceruloplasmin (CP) to ferric iron (Fe³⁺) prior to be loaded onto transferrin (TF) in the circulation (1–4). Iron-loaded TF can then be endocytosed by cells via TF receptor 1 (TFR1), while TF receptor 2 (TFR2) on hepatocytes senses blood iron levels to modulate the expression of a key iron-regulating hormone, hepcidin (2, 3). Gain- or loss-of-function of any of the aforementioned factors such as FPN1, CP, TF, hepcidin, and TFR1/2 alters systemic iron metabolism, leading to either toxicity or anemia due to iron excess or deficiency, respectively, in mice and humans (2, 5–7). However, while most of these factors are synthesized in the endoplasmic reticulum (ER) as either membrane or secreted proteins, molecular details underlying their biogenesis in the ER remained largely unexplored.ER-associated degradation (ERAD) is a principal ER quality-control mechanism that targets misfolded ER proteins for cytosolic proteasomal degradation (8, 9). The SEL1L-HRD1 protein complex represents the most evolutionarily conserved ERAD (10–17). Using conditional and cell type-specific Sel1L-deficient mice, we showed that SEL1L is an obligatory cofactor for the E3 ligase HRD1 (18). Subsequent studies from several laboratories have collectively demonstrated a critical physiological and pathological importance of this ERAD complex in various cell types in energy metabolism, food intake, immunity, gut and kidney homeostasis, cartilage development, and quiescence of hematopoietic stem cells (19–33). However, the significance of SEL1L-HRD1 ERAD in iron metabolism remains unknown.In this study, we report the role of hepatocyte-specific SEL1L-HRD1 ERAD in systemic iron homeostasis by regulating the maturation and turnover of CP in the ER. Mice with hepatocyte-specific Sel1L deficiency have altered basal iron homeostasis and altered response to iron deficiency and overload. Mechanistically, SEL1L-HRD1 ERAD mediates the proteasomal degradation of both endogenous and disease mutants of CP proteins, thereby regulating its abundance in the circulation and limiting their pathogenicity, respectively.     

Importance of interleukin-1 and interleukin-1 receptor antagonist in short-term glucose sensor function in vivo

Background

The importance of the interleukin (IL)-1 cytokine family in inflammation and immunity is well established as a result of extensive in vitro and in vivo studies. In fact, much of our understanding of the in vivo importance of interleukin-1beta (IL-1B) is the result of research utilizing transgenic mice, such as overexpression or deficiencies of the naturally occurring inhibitor of IL-1 known as interleukin-1 receptor antagonist (IL-1RA). For the present studies, we utilized these transgenic mice to determine the role of IL-1B in glucose sensor function in vivo.

Methods

To investigate the role of IL-1B in glucose sensor function in vivo, we compared glucose sensor function in trans-genic mice that (1) overexpressed IL-1RA [B6.Cg-Tg(II1rn)1Dih/J] and (2) are deficient in IL-1RA (B6.129S-Il1rn^tm1Dih/J), with mice that have normal levels of IL-1RA (C57BL/6).

Results

Our studies demonstrated that, during the first 7 days post-sensor implantation (PSI), mice deficient in IL-1RA had extensive inflammation and decreased sensor function when compared to normal or IL-1RA-overexpressing mice.

Conclusion

These data directly support our hypothesis that the IL-1 family of cytokines and antagonists play a critical role in controlling tissue reactions and thereby sensor function in vivo during the first 7 days PSI.     

Body iron metabolism and pathophysiology of iron overload

Iron is an essential metal for the body, while excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. There is a sophisticated balance of body iron metabolism of storage and transport, which is regulated by several factors including the newly identified peptide hepcidin. As there is no passive excretory mechanism of iron, iron is easily accumulated when exogenous iron is loaded by hereditary factors, repeated transfusions, and other diseased conditions. The free irons, non-transferrin-bound iron, and labile plasma iron in the circulation, and the labile iron pool within the cells, are responsible for iron toxicity. The characteristic features of advanced iron overload are failure of vital organs such as liver and heart in addition to endocrine dysfunctions. For the estimation of body iron, there are direct and indirect methods available. Serum ferritin is the most convenient and widely available modality, even though its specificity is sometimes problematic. Recently, new physical detection methods using magnetic resonance imaging and superconducting quantum interference devices have become available to estimate iron concentration in liver and myocardium. The widely used application of iron chelators with high compliance will resolve the problems of organ dysfunction by excess iron and improve patient outcomes.     

ORIGINAL ARTICLE: Pro-hepcidin and iron metabolism parameters in multi-time blood donors

A high number of blood donations may cause iron depletion. The pathophysiology behind this process may involve hepcidin, a recently discovered peptide that acts by inhibiting iron absorption and promoting iron retention in reticuloendothelial macrophages. The aim of this study was to determine serum pro-hepcidin levels and iron metabolism parameters in multi-time blood donors. The study group consisted of 132 multi-time male blood donors and 25 healthy male volunteers (nondonors). Complete blood cell count and iron status including serum iron, ferritin, soluble transferrin receptor (sTfR), total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), erythropoietin and pro-hepcidin (ELISA) were assessed. In blood donors, ferritin level drops markedly in relation to donation frequency (P < 0.001). In contrast, TIBC and UIBC levels increase progressively corresponding to annual donation frequency. Pro-hepcidin concentration increases significantly with the number of donations per year (P = 0.0290). In blood donors having donated blood with the highest frequency per year, pro-hepcidin levels were positively correlated with haemoglobin (R = 0.31, P < 0.05) and negatively with sTfR (R = −0.31, P < 0.05). Pro-hepcidin levels increase in relation to blood donation frequency per year. Longitudinal studies focusing on changes in serum hepcidin levels are required to address the question whether hepcidin may contribute to iron metabolism disturbances in multi-times blood donors.     

测定脑卒中患者血清C反应蛋白及白细胞介素含量的临床意义

目的探讨脑卒中患者血清C反应蛋白(CRP)、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)含量变化及临床意义。方法将96例脑卒中患者分为脑梗死组(56例),脑出血组(40例),同期选择健康体检者35例为对照组,分别检测其治疗前和治疗后5天的血清CRP、IL-1β和IL-6的浓度。根据神经功能损伤程度评分标准将患者又分为轻度损伤组(32例)、中度损伤组(48例)和重度损伤组(16例)。结果脑卒中患者治疗前血清CRPI、L-1β和IL-6明显高于对照组(P<0.01),且治疗后比治疗前明显下降(P<0.05),并随着脑神经功能损害的加重而升高(P<0.05)。结论CRPI、L-1β和IL-6在脑卒中的发病过程中起促进作用,与脑神经受损程度呈正相关。     

重组人胰岛素样生长因子1的促糖代谢作用研究

目的 研究胰岛素样生长因子１对糖代谢的影响。方法 分别以Ｂａｌｂ／ｃ ３Ｔ３成纤维细胞和昆明种小鼠为对象,研究重组人胰岛素样生长因子１的降糖作用。结果 （１）ＩＧＦ１使Ｂａｌｂ／ｃ３Ｔ３细胞培养液和葡萄糖浓度降到对照组的６５％,与胰岛素的降糖能力相似;（２）ＩＧＦ１能使小鼠血糖降到正常值２０％左右,降糖作用呈剂量－效应曲线。     

Effect of ursodeoxycholic acid on liver iron stores and distribution in rats with normal or iron-supplemented diet

Abstract: Iron excess is a potential liver-damaging factor, and bile salts can increase iron digestive absorption and iron biliary excretion. The aim of this study was to investigate in rats the effect of ursodeoxycholic acid, a bile salt used in the treatment of chronic liver disease, on the hepatic iron stores in normal and iron-overload conditions. UDCA was administered by gavage to Sprague-Dawley rats. Iron hyperabsorption and overload were obtained by 5% carbonyl iron addition in diet. Hepatic iron stores and distribution were evaluated by liver iron concentration measurement and histologic assessment, respectively. Whatever the iron content of the diet, liver iron concentration was not modified by UDCA administration compared with the control groups. Iron distribution was not modified by UDCA in rats with normal diet. The total iron score was only transiently lowered by UDCA in iron supplemented rats compared with the control group at 1 month. In conclusion, chronic UDCA administration does not modify liver iron stores and distribution in rats with both normal or increased digestive iron absorption. These data suggest that UDCA is unlikely to increase hepatic iron stores in treated patients and that the benefit of UDCA treatment is probably not related to a decreasing effect of liver iron content.     

Anaemia of chronic disease in AA amyloidosis is associated with allele 2 of the interleukin-1beta-511 promoter gene and raised levels of interleukin-1beta and interleukin-18

OBJECTIVE: In amyloid A (AA) amyloidosis the receptor for advanced glycation end products is a target for the circulating amyloid precursor protein (SAA) resulting in upregulation of the proinflammatory cytokine pathway. Besides inducing hepatic SAA synthesis the interleukin-1 cytokine family is involved in the regulation of haematopoiesis. We therefore studied the relationship between the circulating levels of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18), a new member of the IL-1 complex, as well as polymorphisms within the IL-1 cluster with the occurrence of anaemia in patients with AA amyloidosis. DESIGN, SETTING AND SUBJECTS: The study included 54 adult patients with biopsy-proven reactive amyloidosis allocated into three groups on the basis of haemoglobin (Hb) level: group I included all patients with Hb < 110 g L(-1) (n = 16); group II patients (Hb > 110 g L(-1), n = 16) were selected to match group I patients with respect to sex, age, underlying disease (seropositive, erosive rheumatoid arthritis) and renal function; and group III patients (n = 38) represented all patients (unselected) with Hb > or = 110 g L(-1). Gene polymorphisms were studied by polymerase chain reaction restriction length assay and included the base exchange at position-889 of the IL-1alpha gene, the polymorphic region at position-511 and the polymorphic locus at exon 5, position +3954 of the IL-1beta gene, as well as the IL-1 receptor antagonist (IL-1Ra) exon 2 polymorphism caused by the 86-bp tandem repeats. Plasma IL-1beta, IL-1alpha, IL-18, IL-1 Ra, SAA, ferritin, soluble transferrin receptor and erythropoietin levels were studied by enzyme immunoassays. RESULTS: Circulating IL-beta and IL-18 were significantly raised in the anaemic patients with AA amyloidosis when compared with group II patients (matched, Hb > 110 g L(-1)) as well as group III patients (nonmatched, Hb > or = 110 g L(-1)). A significant inverse relationship was found between IL-1beta and haemoglobin levels, as well as between IL-18 and haemoglobin levels. The frequency of allele 2 (T) of the IL-1beta-511 promoter gene was significantly increased and that of allele 1 (C) decreased in anaemic amyloid patients (group I) when compared with group II and III patients. Circulating IL-1beta levels tended to be higher amongst the IL-1beta-511 allele 2 carriers than amongst the noncarriers, as well as amongst the anaemic amyloid patients filling all criteria of anaemia of chronic disease. CONCLUSION: The occurrence of anaemia in patients with AA amyloidosis is associated with allele 2 (T) of the IL-1beta-511 promoter gene and elevated levels of circulating IL-1beta and IL-18. In AA amyloidosis the raised cytokine levels may generate a vicious cycle leading to accelerated amyloidogenesis, suppression of erythropoiesis and aggravation of the underlying inflammatory disorder.     

Treatment with gallium nitrate: evidence for interference with iron metabolism in vivo.

Gallium, when bound to transferrin, has been previously shown to cause tumor cell cytotoxicity by preventing cellular uptake of transferrin bound iron in vitro. Patients treated with constant infusion gallium nitrate for carcinoma show a rise in serum iron within 6 hr of the start of treatment. Serum iron returns to baseline by 24 hr post-infusion. Atomic analysis of iron and gallium content of Sephadex G-150 fractions of treatment sera indicate that about an equimolar amount of gallium and iron are associated with transferrin. These gallium and iron concentrations result in inhibition of transferrin mediated iron uptake in vitro, and in vivo allow for > 90% saturation of transferrin with metal. All seven patients who completed two courses of gallium therapy exhibited hypochromic microcytic anemia (mean fall in hemoglobin 3.5 grams %). Evidence for red cell iron depletion was confirmed by an increase (mean 3.3-fold) in zinc protoporphyrin levels. Since transferrin receptor increases on gallium treated iron requiring cells in vitro, we assessed cell surface transferrin receptor on peripheral blood lymphocytes by measuring fluorescent transferrin receptor antibody binding. A population of highly transferrin receptor positive cells peaks at 48 hr into the infusion. DNA analysis as well as double staining indicate the majority of transferrin receptor positive cells are unstimulated B lymphocytes. These studies provide the first documentation that constant infusion gallium treatment results in significant interference with iron metabolism and evidence for tissue iron depletion in vivo. These changes may correlate with therapeutic effects of gallium such as tumor response.     

慢性丙型肝炎铁代谢的失调机制

肝脏是人体储存铁离子的主要器官,因此铁离子代谢失常与慢性肝炎密切相关。目前,慢性丙型肝炎(CHC)中铁离子过载的机制并没有完全阐明。铁调素调控非常复杂,依赖于许多变量,包括不同阶段的肝脏炎症情况、转铁蛋白参与的铁离子循环以及胞内铁离子储存等,这些因素都与引起HCV相关肝脏疾病患者中铁离子浓度的变化有关。讨论了系统铁离子稳态的调控、CHC与铁离子失调的关系及诱发CHC铁离子过载的机制。认为深入认识铁离子稳态和相关信号通路之间的关系将促进HCV相关疾病的控制与治疗。