Hepcidin与疾病关系和其临床意义的研究进展

铁是人体必需的微量元素,是血红蛋白、肌红蛋白及多种酶的重要组成成分,广泛地参与氧气输运、氧化还原反应、细胞增殖与分化、基因表达调控等基本生命过程。机体铁稳态对生命体新陈代谢的平衡起着至关重要的作用。铁稳态依赖铁吸收、转运和储存、再循环利用等代谢过程共同调节。铁调素（Hepcidin）是铁代谢调节中最关键的调节分子,成熟的铁调素是一个由25个氨基酸组成的功能性小肽类激素,可以通过调节小肠上皮细胞和巨噬细胞表面的相关铁转运蛋白来调控机体内铁的储存和利用。铁调素同时受到机体铁水平的反馈,免疫应答和红细胞生成等因素的共同调节。许多铁代谢疾病、炎症和各种原因引起的贫血与铁调素的异常表达相关。因此,对于铁调素的检测不但可以反映机体的铁代谢状况,结合其他临床指标还能够辅助诊断和有针对性地检测相关疾病的治疗效果。     

铁代谢调节分子Erythroferrone研究进展

红细胞来源的erythroferrone (ERFE)是最近发现的一种重要的铁代谢调节蛋白。在应激红细胞生成过程中,促红细胞生成素（EPO）能够促使骨髓有核红细胞分泌ERFE,从而抑制肝脏铁调素合成,进而稳定铁释放蛋白（FPN1）的水平,最终增加铁的吸收和动员。铁是红细胞生成不可缺少的重要原料之一,当红细胞生成增加时,需要充足的铁来合成血红素和血红蛋白。血液中的ERFE在红细胞生成时为保障稳定的铁供应发挥着重要作用。本文就ERFE的发现、基因结构和蛋白质结构、分布,ERFE在糖脂代谢、红细胞生成和铁代谢中的作用,以及ERFE功能异常与β-地中海贫血和慢性肾脏疾病等疾病的联系,ERFE在基础研究与临床检测中的应用,尤其是EPO/ERFE/hepcidin-FPN1在铁代谢调控中的作用机制展开论述,以期为靶向治疗铁代谢失衡疾病提供参考。     

铁过载与骨质疏松的关系

近来研究表明,铁过载与骨质疏松有密切的关系。遗传性血色素沉着症和地中海贫血症等铁代谢紊乱的疾病患者中都伴随有不同程度的骨质疏松现象。另外,长期在轨飞行环境下,航天员出现机体铁沉积现象,同时,骨丢失情况十分严重,每月的骨丢失量约与地面上绝经后妇女每年的骨丢失量相当。铁水平升高能够抑制成骨细胞的分化,降低成骨细胞功能,成骨能力下降,骨形成受到抑制。铁沉积的同时,能够促进破骨细胞活性,增强骨吸收的能力,造成机体骨量减少,导致骨质疏松。铁调素能够作用于成骨细胞,随着铁调素剂量的增加,成骨细胞中与骨形成相关的基因表达量明显升高。铁调素还能作用于破骨细胞,促进破骨细胞的分化。在预防和治疗骨质疏松方面,有实验证明,铁螯合剂和铁调素都有治疗骨质疏松的作用。利用铁调素调节机体铁代谢平衡,降低铁过载程度,为日后临床治疗骨质疏松提供了理论支持。     

铁代谢红细胞系调节因子与铁稳态

红细胞合成是人类和其他脊椎动物最耗铁的生理过程,对机体铁稳态具有重要调节作用。Erythroferrone（ERFE）是红细胞系来源的调节铁调素的主要激素。当机体存在应激性红细胞合成时,ERFE合成增加,铁调素表达受抑,可促进机体铁吸收和储铁动员,满足红细胞合成对铁的需求,但在无效红细胞生成疾病中,通过此作用也导致了铁过载的发生。ERFE抑制肝细胞合成铁调素的作用机制尚不清楚,但至少部分地依赖BMP/SMAD信号通路。ERFE对铁代谢障碍性疾病和红细胞生成紊乱性贫血有重要的诊断及治疗价值。     

EPO治疗慢性肾衰患者对铁调素、FDP及红细胞免疫的影响

为了探讨促红细胞生成素(EPO)治疗慢性肾衰患者对铁调素、纤维蛋白原降解产物(FDP)及红细胞免疫水平的影响。选取我院2014年1月至2016年1月间收治的30例规律使用EPO治疗的肾功能不全肾衰期患者作为研究对象进行自身对照研究,患者使用EPO治疗12周,分别于治疗前、治疗后检测并比较血清铁调素、FDP、红细胞免疫水平等指标。研究显示,相较于治疗前,30例患者接受治疗后血清中的RBC、Hb、TRF、PA、血清铁和RBC-C3b RR比例均发生显著性提高,差异具有统计学意义(p0.05);而hs-CRP、FDP、铁调素水平以及RBC-ICR比例发生显著性降低,差异具有统计学意义(p0.05);但血清中Scr水平无明显变化,差异不具有统计学意义(p0.05)。因此,EPO治疗慢性肾衰患者能通过调节血清铁调素水平纠正肾性贫血,同时改善患者的红细胞免疫功能及营养状态。     

铁紊乱相关疾病的研究进展

铁作为一种必需的营养元素,在哺乳动物体内的重要作用越来越为人们所重视。动物体内存在着严格的铁代谢调节机制,以确保体内铁始终处于正常生理水平。如果铁代谢失调、体内铁缺乏或过负荷均会导致各种临床疾病。研究发现,肝脏抗菌多肽(hepcidin)很可能是一种控制小肠铁吸收及调节体内铁稳态的关键物质,是一种极为重要的铁调节激素。本文综述了铁的生理作用、铁缺乏引起的疾病(如:缺铁性贫血和儿童神经系统疾病)和铁过负荷引起的疾病(如:肝损伤、心血管疾病、帕金森病和癌症等),并对如何利用现代化技术手段在基因水平开展铁紊乱相关疾病的治疗做了展望。     

脂肪组织在铁稳态调节中的作用以及肥胖的铁缺乏机制

机体铁稳态的维持对正常生理功能至关重要。铁调素和铁调素调节蛋白在维持铁稳态中发挥重要作用。近来,丝氨酸蛋白酶基质-2在铁稳态中的作用越来越受到重视。此外,肥胖与铁缺乏的发生密切相关。一方面,肥胖人群脂肪组织高水平分泌白介素-6(interleukin-6, IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)以及瘦素等脂肪因子,这些脂肪因子能够调节铁调素和铁调素调节蛋白表达;另一方面,肥胖个体脂肪组织也可直接表达铁调素与铁调素调节蛋白。运动作为一种非侵入性干预手段在调节肥胖与铁缺乏中可能发挥重要作用。本文将对近年来文献进行整理,以期能够为铁稳态维持以及肥胖与铁缺乏的机制提供一些新的视角。     

铁调素调节蛋白(HJV)———一个新的铁代谢调节蛋白

铁调素调节蛋白 (hemojuvelin,HJV) 是最近发现的一种重要的铁代谢调节蛋白. HJV基因突变是年轻型血色素沉着症 (Juvenile hemochromatosis,JH ) 的重要原因之一. 研究显示,HJV可能是一种极为重要的铁调素 (hepcidin) 表达的调节蛋白,通过参与铁调素表达的调节从而在铁代谢中发挥重要作用.     

Hepcidin研究进展

Hepcidin是肝脏特异性表达的一种小分子抗菌肽,是铁代谢的负调节激素。与炎症性贫血、遗传性血色沉着病等疾病的发病机制密切相关。证据显示,Hepcidin直接抑制肠上皮细胞铁吸收和诱导单核巨噬细胞铁滞留。同时,Hepcidin还具有广谱抗菌活性,与固有免疫密切相关。铁超载、感染、炎症及细胞因子可诱导Hepcidin表达,而贫血和缺氧则抑制其表达。Hepcidin的发现及其相关的铁离子运输机制的研究,将为铁离子吸收及分配的铁稳态调节和炎症性贫血、遗传性血色沉着病中的铁代谢障碍的分子机制探索开辟新的途径。本文就Hepcidin的分子特征、表达调控及生物学功能等方面研究进展进行综述。     

Hepcidin在哺乳类及鱼类中的表达和作用

Hepcidin也称为铁调素,是肝脏特异性表达的一种阳离子小分子抗菌肽,具有抑制多种细菌、真菌、病毒和原生动物生长繁殖的作用,是机体天然免疫的一种效应分子;同时也是一种信号分子,参与机体铁代谢,通过直接抑制肠上皮细胞铁吸收和单核巨噬细胞铁释放调节机体铁平衡,与炎症性贫血、遗传性血色素沉着病等铁代谢紊乱性疾病的发病机制密切相关。脂多糖（LPS）、铁超载和病原体可诱导hepcidin表达,而贫血和缺氧可下调其表达。目前,鱼类hepcidin的研究也成为热点,但主要集中在hepcidin的抗菌活性方面,有关其在鱼类铁代谢方面的功能仍需要进一步研究。     

Hepcidin的生物学特性及其研究进展

Hepcidin是一种由肝脏合成的富含半胱氨酸的小分子肽。近几年的研究证实hepcidin对于调节机体铁离子的代谢平衡发挥着重要的作用,其可抑制肠道铁吸收和单核巨噬细胞系统铁释放。此外,除了机体铁状况,感染、炎症、贫血和缺氧等原因也会改变hepcidin的表达水平。通过对hepcidin的分子生物学特点、表达调控及生物活性、医学及药用价值等方面研究进展的概述,对采用基因工程的方法生产hepcidin进行了评述及展望。     

Plasma Concentrations of Hepcidin in Anemic Zimbabwean Infants

Objective

Anemia in infancy is a global public health problem. We evaluated the relative contributions of iron deficiency and inflammation to infant anemia.

Methods

We measured plasma hepcidin, ferritin, soluble transferrin receptor (sTfR), alpha-1-acid glycoprotein and C-reactive protein (CRP) by ELISA on archived plasma from 289 HIV-unexposed anemic or non-anemic Zimbabwean infants at ages 3mo, 6mo and 12mo. Among anemic infants, we determined the proportion with iron-deficiency anemia (IDA) and anemia of inflammation (AI). We undertook regression analyses of plasma hepcidin and anemia status, adjusting for sex, age and birthweight.

Results

Anemic infants at 3mo were more stunted and had higher CRP (median 0.45 vs 0.21mg/L; P = 0.037) and hepcidin (median 14.7 vs 9.7ng/mL; P = 0.022) than non-anemic infants, but similar levels of ferritin and sTfR; 11% infants had IDA and 15% had AI. Anemic infants at 6mo had higher hepcidin (median 7.9 vs 4.5ng/mL; P = 0.016) and CRP (median 2.33 vs 0.32mg/L; P<0.001), but lower ferritin (median 13.2 vs 25.1μg/L; P<0.001) than non-anemic infants; 56% infants had IDA and 12% had AI. Anemic infants at 12mo had lower ferritin (median 3.2 vs 22.2μg/L; P<0.001) and hepcidin (median 0.9 vs 1.9ng/mL; P = 0.019), but similar CRP levels; 48% infants had IDA and 8% had AI. Comparing anemic with non-anemic infants, plasma hepcidin was 568% higher, 405% higher and 64% lower at 3mo, 6mo and 12mo, respectively, after adjusting for sex and birthweight (all p<0.01). Plasma hepcidin declined significantly with age among anemic but not non-anemic infants. Girls had 61% higher hepcidin than boys, after adjusting for age, anemia and birthweight (p<0.001).

Conclusion

Anemia is driven partly by inflammation early in infancy, and by iron deficiency later in infancy, with plasma hepcidin concentrations reflecting the relative contribution of each. However, there is need to better characterize the drivers of hepcidin during infancy in developing countries.     

Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin,anemia response and disease activity in rheumatoid arthritis patients

Introduction

Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life. Upregulation of hepcidin by inflammatory cytokines has been implicated in AI. In this study, we evaluated and compared the effects of IL-6 and TNF-α blocking therapies on anemia, disease activity, and iron-related parameters including serum hepcidin in RA patients.

Methods

Patients (n = 93) were treated with an anti-IL-6 receptor antibody (tocilizumab) or TNF-α inhibitors for 16 weeks. Major disease activity indicators and iron-related parameters including serum hepcidin-25 were monitored before and 2, 4, 8, and 16 weeks after the initiation of treatment. Effects of tocilizumab and infliximab (anti-TNF-α antibody) on cytokine-induced hepcidin expression in hepatoma cells were analyzed by quantitative real-time PCR.

Results

Anemia at base line was present in 66% of patients. Baseline serum hepcidin-25 levels were correlated positively with serum ferritin, C-reactive protein (CRP), vascular endothelial growth factor (VEGF) levels and Disease Activity Score 28 (DAS28). Significant improvements in anemia and disease activity, and reductions in serum hepcidin-25 levels were observed within 2 weeks in both groups, and these effects were more pronounced in the tocilizumab group than in the TNF-α inhibitors group. Serum hepcidin-25 reduction by the TNF-α inhibitor therapy was accompanied by a decrease in serum IL-6, suggesting that the effect of TNF-α on the induction of hepcidin-25 was indirect. In in vitro experiments, stimulation with the cytokine combination of IL-6+TNF-α induced weaker hepcidin expression than did with IL-6 alone, and this induction was completely suppressed by tocilizumab but not by infliximab.

Conclusions

Hepcidin-mediated iron metabolism may contribute to the pathogenesis of RA-related anemia. In our cohort, tocilizumab was more effective than TNF-α inhibitors for improving anemia and normalizing iron metabolism in RA patients by inhibiting hepcidin production.     

Hepcidin: a direct link between iron metabolism and immunity

Hepcidin, originally discovered in urine as a bactericidal peptide synthesized by hepatocytes was later proved to be a key regulator of iron metabolism at the whole body level, namely, in conditions of altered iron demand such as the increased or decreased total amount of body iron, inflammation, hypoxia and anemia. The major mechanism of hepcidin function seems to be the regulation of transmembrane iron transport. Hepcidin binds to its receptor, protein ferroportin, which serves as a transmembrane iron channel enabling iron efflux from cells. The hepcidin-ferroportin complex is then degraded in lysosomes and iron is locked inside the cells (mainly enterocytes, hepatocytes and macrophages). This leads to lowering of iron absorption in the intestine and to a decrease in serum iron concentration. Utilizing this mechanism, hepcidin regulates serum iron levels during inflammation, infection and possibly also in cancer. Under these conditions iron is shifted from circulation into cellular stores in hepatocytes and macrophages, making it less available for invading microorganisms and tumor cells. In anemia and hypoxia, hepcidin regulates the availability of iron for erythropoiesis. Hepcidin or hepcidin-related therapeutics could find a place in the treatment of various diseases such as hemochromatosis and anemia of chronic disease.     

Low Serum Hepcidin in Patients with Autoimmune Liver Diseases

Hepcidin, a liver hormone, is important for both innate immunity and iron metabolism regulation. As dysfunction of the hepcidin pathway may contribute to liver pathology, we analysed liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases. Hepcidin mRNA levels were determined in liver biopsies obtained from 126 patients with HCV (n = 21), HBV (n = 23), autoimmune cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis; PBC/PSC; n = 34), autoimmune hepatitis (AIH; n = 16) and non-alcoholic fatty liver disease (NAFLD; n = 32). Sera sampled on the biopsy day from the same patients were investigated for serum hepcidin levels. Hepatic hepcidin mRNA levels correlated positively with ferritin and negatively with serum γ-GT levels. However, no correlation was found between serum hepcidin and either ferritin or liver hepcidin mRNA. Both serum hepcidin and the serum hepcidin/ferritin ratio were significantly lower in AIH and PBC/PSC patients’ sera compared to HBV, HCV or NAFLD (P<0.001 for each comparison) and correlated negatively with serum ALP levels. PBC/PSC and AIH patients maintained low serum hepcidin during the course of their two-year long treatment. In summary, parallel determination of liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases shows that circulating hepcidin and its respective ratio to ferritin are significantly diminished in patients with autoimmune liver diseases. These novel findings, once confirmed by follow-up studies involving bigger size and better-matched disease subgroups, should be taken into consideration during diagnosis and treatment of autoimmune liver diseases.     

Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.     

The dietary flavonoid myricetin regulates iron homeostasis by suppressing hepcidin expression

Hepcidin, a master regulator of iron homeostasis, is a promising target in treatment of iron disorders such as hemochromatosis, anemia of inflammation and iron-deficiency anemia. We previously reported that black soybean seed coat extract could inhibit hepcidin expression. Based on this finding, we performed a screen in cultured cells in order to identify the compounds in black soybeans that inhibit hepcidin expression. We found that the dietary flavonoid myricetin significantly inhibited the expression of hepcidin both in vitro and in vivo. Treating cultured cells with myricetin decreased both HAMP mRNA levels and promoter activity by reducing SMAD1/5/8 phosphorylation. This effect was observed even in the presence of bone morphogenic protein-6 (BMP6) and interleukin-6 (IL-6), two factors that stimulate hepcidin expression. Furthermore, mice that were treated with myricetin (either orally or systemically) had reduced hepatic hepcidin expression, decreased splenic iron levels and increased serum iron levels. Notably, myricetin-treated mice increased red blood cell counts and hemoglobin levels. In addition, pretreating mice with myricetin prevented LPS-induced hypoferremia. We conclude that myricetin potently inhibits hepcidin expression both in vitro and in vivo, and this effect is mediated by altering BMP/SMAD signaling. These experiments highlight the feasibility of identifying and characterizing bioactive phytochemicals to suppress hepcidin expression. These results also suggest that myricetin may represent a novel therapy for treating iron deficiency-related diseases.     

Known and potential roles of transferrin in iron biology

Transferrin is an abundant serum metal-binding protein best known for its role in iron delivery. The human disease congenital atransferrinemia and animal models of this disease highlight the essential role of transferrin in erythropoiesis and iron metabolism. Patients and mice deficient in transferrin exhibit anemia and a paradoxical iron overload attributed to deficiency in hepcidin, a peptide hormone synthesized largely by the liver that inhibits dietary iron absorption and macrophage iron efflux. Studies of inherited human disease and model organisms indicate that transferrin is an essential regulator of hepcidin expression. In this paper, we review current literature on transferrin deficiency and present our recent findings, including potential overlaps between transferrin, iron and manganese in the regulation of hepcidin expression.