肝硬化患者肝组织中hepcidin基因的表达水平及其对铁代谢的影响
摘要
背景和目的:Hepcidin是由肝脏分泌的小分子肽,目前已经成为公认的调控机体内铁吸收和铁平衡的关键性激素。本研究旨在了解hepcidin基因在肝硬化患者中的表达水平及其对铁代谢的影响。方法:采用化学发光法分别检测肝硬化组和对照组的血清铁蛋白的含量。通过RT-PCR ( reverse transcription-polymerase chain reaction)技术测定肝组织中的hepcidin基因的表达水平。最后对所有测得的数据进行统计学分析。结果:肝硬化患者肝组织的hepcindin的表达较之对照组的表达显著增高(p<0.01),肝硬化组血清铁蛋白的含量也显著高于对照组(p<0.01)。而且,hepcidin/β-action在肝硬化组和对照组中的表达与血清铁蛋白的含量具有显著相关性(p<0.01)。结论:1.通过研究发现hepcidin基因在肝硬化患者中的表达显著增加,hepcidin抑制了肠道对铁的吸收以及巨噬细胞、肝脏等组织细胞中铁的输出,使铁锁定在网状内皮系统的巨噬细胞和肝脏等组织细胞内,引起了铁的循环利用障碍,从而导致外周血的铁含量不足;同时,因为它抑制了肝细胞中铁的输出,也是使肝脏维持铁的高含量状态的原因之一,加重了肝损伤。2.从研究的结果中可以推测:在肝硬化状态下,体内的高储备的铁或是铁蛋白状态对hepcidin分泌的刺激作用占主导地位,相对而言贫血对hepcidin分泌的抑制作用却没有表现出来。
Backgroud and aims: Hepcidin is a small molecular peptide which secreted by the liver. At present, it is already thought to be the central regulator of iron absorption and iron balance in the organism. This research is for the purpose of understanding the expression level of the hepcidin gene and its effects on iron metabolism in patients with liver cirrhosis. Methods: Using the photochmemistry law to examine 12 examples liver cirrhosis patients' as well as the healthy control individuals' serum ferritin content separately, and using the RT-PCR(reverse transcription-polymerase chain reaction) technology to examine the expression level of the hepcidin gene in liver tissues, taking actin (β-actin) as internal control. Finally, analysis the data which all obtains in the study using statistics analysis. Results: In patients with liver cirrhosis, the serum ferritin content is significantly higher than the control individuals (p<0.01). The liver hepcidin/β-actin ratio in patients with liver cirrhosis compared with control individuals is significantly higher (p<0.01) too. And the ratio correlates significantly with serum ferritin level in patients with liver cirrhosis and control individuals (p<0.01) . Conclusions: 1. Through the study found that the expression of the hepcidin gene in patients with liver cirrhosis increases significantly. Hecidin can inhibit the intestinal absorption of iron as well as the output of iron in macrophage, liver, and other tissues, and cause iron to be locked in macrophages of the reticuloendouthelial system, liver, and other tissues. That caused the circulation and utilization of iron disordered, leading to the iron content shortage in blood. At the same time, because it can inhibite the output of iron of the liver cells, so that it becomes one of the reasons that the liver can maintain the high iron content state, and the state aggravate liver injury. 2. From the results of the study ,we can have an inference that under the liver cirrhosis condition, the overloaded iron or serum ferritin of the body occupies the main status to stimulate the hepcidin secretion, and the anemia cannot display the effects on inhibiting the hepcidin secretion.
Backgroud and aims: Hepcidin is a small molecular peptide which secreted by the liver. At present, it is already thought to be the central regulator of iron absorption and iron balance in the organism. This research is for the purpose of understanding the expression level of the hepcidin gene and its effects on iron metabolism in patients with liver cirrhosis. Methods: Using the photochmemistry law to examine 12 examples liver cirrhosis patients' as well as the healthy control individuals' serum ferritin content separately, and using the RT-PCR(reverse transcription-polymerase chain reaction) technology to examine the expression level of the hepcidin gene in liver tissues, taking actin (β-actin) as internal control. Finally, analysis the data which all obtains in the study using statistics analysis. Results: In patients with liver cirrhosis, the serum ferritin content is significantly higher than the control individuals (p<0.01). The liver hepcidin/β-actin ratio in patients with liver cirrhosis compared with control individuals is significantly higher (p<0.01) too. And the ratio correlates significantly with serum ferritin level in patients with liver cirrhosis and control individuals (p<0.01) . Conclusions: 1. Through the study found that the expression of the hepcidin gene in patients with liver cirrhosis increases significantly. Hecidin can inhibit the intestinal absorption of iron as well as the output of iron in macrophage, liver, and other tissues, and cause iron to be locked in macrophages of the reticuloendouthelial system, liver, and other tissues. That caused the circulation and utilization of iron disordered, leading to the iron content shortage in blood. At the same time, because it can inhibite the output of iron of the liver cells, so that it becomes one of the reasons that the liver can maintain the high iron content state, and the state aggravate liver injury. 2. From the results of the study ,we can have an inference that under the liver cirrhosis condition, the overloaded iron or serum ferritin of the body occupies the main status to stimulate the hepcidin secretion, and the anemia cannot display the effects on inhibiting the hepcidin secretion.
引文
[1] Ritland S, Aaseth J. Trace elements and the liver [J]. J Hepatol, 1987, 5(1): 118～122.
[2] 李增禧,梁业成. 铁是生命攸关的微量元素[J]. 广东省微量元素科学,1994,1(3): 54～55.
[3] 黄聪武,白岚. 铁过载和肝脏疾病[J]. 第一军医大学学报,2002,22(4): 370～371.
[4] Ali M, Fayemi A O, Braun E V, et al. Dissociation between hepatosplenic and marrow iron in liver cirrhosis [J]. Arch Pathol Lab Med, 1982, 106(4): 200～204.
[5] 李闻,鲍善芬,程留芳等. 11 例肝硬化患者出入肝血中铁铜锌含量变化及其意义[J]. 军医进修学院学报,1997, 18(3): 197～199.
[6] Kulaksiz H, Gehrke S G, Janetzko A, et al. Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia [J]. Gut, 2004, 53(5): 735～743.
[7] Krause A, Neitz S, Magert H J, et a1. LEAP-l, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity [J]. FEBS Lett, 2000, 480(2-3): l47～l50.
[8] Park C H, Valore E V, Waring A J, et a1. Hepcidin, a urinary antimicrobial peptide synthesized in the Liver [J]. J Biol Chem ,2001,276(11):7806～78l0.
[9] Ilyin G, Courselaud B, Troadec M B, et a1. Comparative analysis of mouse hepcidin 1 and 2 genes: evidence for different patterns of expression and coinducibility during iron overlaod [J]. FEBS Lett, 2003, 542(1-3): 22～26.
[10] Weinstein D A, Roy C N, Fleming M D, et a1. Inappropriate expression of hepcidin is associated with iron refractory anemia: implication for the anemia of chronic disease [J]. Blood, 2002, 100(10): 3776～3781.
[11] Hunter H N, Fulton D B, Ganz T, et a1. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis [J]. J Biol Chem, 2002, 277(40): 37597～376603.
[12] Feder J N, Gnirke A, Thomas W, et a1. A nove1 MHC class I-1ike gene is mutated in patients with hereditary haemochromastosis [J]. Nat Crenet, 1996, 13(4): 399～408.
[13] Kawabata H, Yang R, Hirama T, et a1. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family [J]. J Biol Chem, 1999, 274(30), 20826～20832.
[14] Sharma N, Butterworth J, Cooper B T, et a1. The emerging role of the liver in iron metabolism [J]. Am J Gastroentero1, 2005, 100(1): 201～206.
[15] Fleming R E. Advances in understanding the molecular basis for the regulation of dietary iron absorption [J]. Curr Opin Gastroentero1, 2005, 21(2): 201～206.
[16] Yeh K Y, Yeh M, Glass J. Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the Rat [J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286(3): 385～394.
[17] Ganz T. Hepcidin: A peptide hormone at the interface of innate immunity and iron metabolism [J]. Curr Top Microbiol Immunol, 2006, 306: l83～l98.
[18] Nemeth E, Tuttle M S, Powelson J, et a1. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization [J]. Science, 2004, 306(5704): 2090～2093
[19] Frazer D M, Wilkins S J, Becker E M, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats [J]. Gastroenterology, 2002, 123(3): 835～844.
[20] Frazer D M, Anderson G J. The orchestration of body iron intake: how and where do enterocytes receive their cues? [J]. Blood Cells Mol Dis. 2003, 30(3): 288～297.
[21] Jurczyk K, Wawrzynowicz-Syczewska M, Boron-Kaczmarska A, et a1. Serum iron parameters in patients with alcoholic and chronic cirrhosis and hepatitis [J]. Med Sci Monit, 2001, 7(5): 962～965.
[22] 徐杰,段正军. SF RIA 在肝硬化时的临床意义[J]. 放射免疫学杂志,2007,20(2): 127.
[23] Nemeth E, Valore E V, Territo M, et a1. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein [J]. Blood, 2003, 101(7): 2461～2463.
[24] Merryweather-Clarke A T, Cadet E, Bomford A, et a1. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis [J]. Hum Mol Genet, 2003, 12(17): 2241～2247.
[25] Nicolas G, Viatte L, Lou D Q, et a1. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis [J]. Nat Genet, 2003, 34(1): 97～101.
[26] 马勇,徐又佳,王爱东,等. 大鼠骨质疏松模型中肝脏 Hepcidin 基因表达的初步研究[J]. 苏州大学学报(医学版),2006,26(3): 367～369.
[27] Kulaksiz H, Theilig H, Bachmann S, et al. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the kidney [J]. J Endocrinol, 2005, 184(2): 361～370.
[28] Detivaud L, Nemeth E, Boudiema K, et a1. Hepcidin levels in humans are correlate with pepatic iron stores, hemoglobin levels and hepatic function [J]. Blood, 2005, 106(2): 746～748.
[29] 许晓红,李淑兰,朱心智. 肝硬化患者血清 SF、AKP 及 7-GT 检测的临床意义[J]. 医学文选,2005,24(1): 15～16.
[30] 曹治宸,白玉,杨学农,等. 乙型肝炎肝损伤中铁代谢异常的研究[J]. 中华肝脏病杂志,2001,9(1): 37～39.
[31] Pigeon C, Ilyin G, Courselaud B, et a1. A new mouse liver specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload [J]. J Biol Chem, 2001, 276(11): 7811～7819.
[32] Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia,and inflammation [J]. J Clin Invest, 2002, 110(7): 1037～1044.
[1] Krause A, Neitz S, Magert H J ,et a1. LEAP-l,a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity [J]. FEBS Lett, 2000, 480(2-3): l47～150.
[2] Park C H, Valore E V, Waring A J, et a1. Hepcidin,a urinary antimicrobial peptide synthesized in the liver [J]. J Biol Chem, 2001, 276(11): 7806～78l0.
[3] Hunter H N, Fulton D B, Ganz T, et a1. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis [J]. J Biol Chem, 2002, 277(40): 37597～37603.
[4] Ilyin G, Courselaud B, Troadec M B, et a1. Comparative analysis of mouse hepcidin 1 and 2 genes: evidence for different patterns of expression and coinducibility during iron overload [J]. FEBS Lett, 2003, 542(1-3): 22～26.
[5] Pigeon C, Ilyin G, Courselaud B, et a1. A new mouse liver specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload [J]. J Biol Chem, 2001, 276(11): 7811～7819.
[6] Nicolas G, Bennoun M, Devaux I, et a1. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2(USF2) Knockout Mice[J]. Proc Natl Acad Sci USA, 2001, 98(15): 8780～8785.
[7] Ganz T. Hepcidin: A peptide hormone at the interface of innate immunity and iron metabolism [J]. Curr Top Microbiol Immunol, 2006, 306: l83～l98.
[8] Nicolas G, Chauvet C,Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation [J]. J Clin Invest, 2002, 110(7): 1037～1044.
[9] Nemeth E, Tuttle M S, Powelson J, et a1. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization [J]. Science, 2004, 306(5704): 2090～2093.
[10] Detivaud L, Nemeth E, Boudjema K, et a1. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels and hepatic function [J]. Blood, 2005, 106(2): 746～748.
[11] Ganz T. Hepcidin: a regulator of intestinal iron absorption and iron recycling by macrophages [J]. Best Pract Res Clin Haematol, 2005, 18(2): 171～182.
[12] Yeh K Y, Yeh M, Glass J. Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat [J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286(3): 385～394.
[13] Frazer D M, Wilkins S J, Becker E M, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats [J]. Gastroenterology, 2002, 123(3): 835～844.
[14] Frazer D M, Anderson G J. The orchestration of body iron intake: how and where do enterocytes receive their cues? [J]. Blood Cells Mol Dis, 2003, 30(3): 288～297.
[15] Weinstein D A, Roy C N, Fleming M D, et a1. Inappropriate expression of hepcidin is associated with iron refractory anemia: implication for the anemia of chronic disease [J]. Blood, 2002, 100(10): 3776～3781.
[16] Courselaud B, Pigeon C, Inoue Y, et al. C/EBPa regulates hepatic transcription of hepcidin,an antimicrobial peptide and regulator of iron metabolism [J]. J Biol Chem, 2002, 277(43): 41163～41170.
[17] Lee P, Peng H, Gelbart T, et al. The IL-6 and lipopolysaccharide induced transcription of hepcidin in HFE,transferrin receptor 2 and beta-2 microglogbulin-deficint hepatocytes [J]. Proc Natl Acad Sci USA, 2004, 101(25): 9263～9265.
[18] Lee P, Peng H, Gelban T, et a1. Regulation of hepcidin transcription by interleukin-1 and interleukin-6 [J]. Proc Natl Acad Sci USA, 2004, 102(6): 1906～1910.
[19] Kulaksiz H, Theilig F, Bachmann S, et al. The iron-regulatory peptide hormone hepcidin: expresion and cellular localization in mammalian kidney [J]. J Endocrinol, 2005, 184(2): 361～370.
[20] Ali M, Fayemi A O, Braun E V, et al. Dissociation between hepatosplenic and marrow iron in liver cirrhosis [J]. Arch Pathol Lab Med, 1982, 106(4): 200～204.
[21] 李闻,黄昌霞,李维华,等. 肝癌肝硬化组织中铁铜的分布及其意义[J]. 中华物理医学杂志,1995,17(1): 1～4.
[22] 李闻,鲍善芬,程留芳等. 11例肝硬化患者出入肝血中铁铜锌含量变化及其意义[J]. 军医进修学院学报,1997,18(3): 197～199.
[23] 于丽红,孙胜菲.70例肝硬化患者IL-6和TNF-α的临床研究[J]. 长春中医药大学学报,2006,22(4): 50.
[24] 徐杰,段正军. SF RIA在肝硬化时的临床意义[J]. 放射免疫学杂志,2007,20(2): 127.
[2] 李增禧,梁业成. 铁是生命攸关的微量元素[J]. 广东省微量元素科学,1994,1(3): 54～55.
[3] 黄聪武,白岚. 铁过载和肝脏疾病[J]. 第一军医大学学报,2002,22(4): 370～371.
[4] Ali M, Fayemi A O, Braun E V, et al. Dissociation between hepatosplenic and marrow iron in liver cirrhosis [J]. Arch Pathol Lab Med, 1982, 106(4): 200～204.
[5] 李闻,鲍善芬,程留芳等. 11 例肝硬化患者出入肝血中铁铜锌含量变化及其意义[J]. 军医进修学院学报,1997, 18(3): 197～199.
[6] Kulaksiz H, Gehrke S G, Janetzko A, et al. Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia [J]. Gut, 2004, 53(5): 735～743.
[7] Krause A, Neitz S, Magert H J, et a1. LEAP-l, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity [J]. FEBS Lett, 2000, 480(2-3): l47～l50.
[8] Park C H, Valore E V, Waring A J, et a1. Hepcidin, a urinary antimicrobial peptide synthesized in the Liver [J]. J Biol Chem ,2001,276(11):7806～78l0.
[9] Ilyin G, Courselaud B, Troadec M B, et a1. Comparative analysis of mouse hepcidin 1 and 2 genes: evidence for different patterns of expression and coinducibility during iron overlaod [J]. FEBS Lett, 2003, 542(1-3): 22～26.
[10] Weinstein D A, Roy C N, Fleming M D, et a1. Inappropriate expression of hepcidin is associated with iron refractory anemia: implication for the anemia of chronic disease [J]. Blood, 2002, 100(10): 3776～3781.
[11] Hunter H N, Fulton D B, Ganz T, et a1. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis [J]. J Biol Chem, 2002, 277(40): 37597～376603.
[12] Feder J N, Gnirke A, Thomas W, et a1. A nove1 MHC class I-1ike gene is mutated in patients with hereditary haemochromastosis [J]. Nat Crenet, 1996, 13(4): 399～408.
[13] Kawabata H, Yang R, Hirama T, et a1. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family [J]. J Biol Chem, 1999, 274(30), 20826～20832.
[14] Sharma N, Butterworth J, Cooper B T, et a1. The emerging role of the liver in iron metabolism [J]. Am J Gastroentero1, 2005, 100(1): 201～206.
[15] Fleming R E. Advances in understanding the molecular basis for the regulation of dietary iron absorption [J]. Curr Opin Gastroentero1, 2005, 21(2): 201～206.
[16] Yeh K Y, Yeh M, Glass J. Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the Rat [J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286(3): 385～394.
[17] Ganz T. Hepcidin: A peptide hormone at the interface of innate immunity and iron metabolism [J]. Curr Top Microbiol Immunol, 2006, 306: l83～l98.
[18] Nemeth E, Tuttle M S, Powelson J, et a1. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization [J]. Science, 2004, 306(5704): 2090～2093
[19] Frazer D M, Wilkins S J, Becker E M, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats [J]. Gastroenterology, 2002, 123(3): 835～844.
[20] Frazer D M, Anderson G J. The orchestration of body iron intake: how and where do enterocytes receive their cues? [J]. Blood Cells Mol Dis. 2003, 30(3): 288～297.
[21] Jurczyk K, Wawrzynowicz-Syczewska M, Boron-Kaczmarska A, et a1. Serum iron parameters in patients with alcoholic and chronic cirrhosis and hepatitis [J]. Med Sci Monit, 2001, 7(5): 962～965.
[22] 徐杰,段正军. SF RIA 在肝硬化时的临床意义[J]. 放射免疫学杂志,2007,20(2): 127.
[23] Nemeth E, Valore E V, Territo M, et a1. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein [J]. Blood, 2003, 101(7): 2461～2463.
[24] Merryweather-Clarke A T, Cadet E, Bomford A, et a1. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis [J]. Hum Mol Genet, 2003, 12(17): 2241～2247.
[25] Nicolas G, Viatte L, Lou D Q, et a1. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis [J]. Nat Genet, 2003, 34(1): 97～101.
[26] 马勇,徐又佳,王爱东,等. 大鼠骨质疏松模型中肝脏 Hepcidin 基因表达的初步研究[J]. 苏州大学学报(医学版),2006,26(3): 367～369.
[27] Kulaksiz H, Theilig H, Bachmann S, et al. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the kidney [J]. J Endocrinol, 2005, 184(2): 361～370.
[28] Detivaud L, Nemeth E, Boudiema K, et a1. Hepcidin levels in humans are correlate with pepatic iron stores, hemoglobin levels and hepatic function [J]. Blood, 2005, 106(2): 746～748.
[29] 许晓红,李淑兰,朱心智. 肝硬化患者血清 SF、AKP 及 7-GT 检测的临床意义[J]. 医学文选,2005,24(1): 15～16.
[30] 曹治宸,白玉,杨学农,等. 乙型肝炎肝损伤中铁代谢异常的研究[J]. 中华肝脏病杂志,2001,9(1): 37～39.
[31] Pigeon C, Ilyin G, Courselaud B, et a1. A new mouse liver specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload [J]. J Biol Chem, 2001, 276(11): 7811～7819.
[32] Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia,and inflammation [J]. J Clin Invest, 2002, 110(7): 1037～1044.
[1] Krause A, Neitz S, Magert H J ,et a1. LEAP-l,a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity [J]. FEBS Lett, 2000, 480(2-3): l47～150.
[2] Park C H, Valore E V, Waring A J, et a1. Hepcidin,a urinary antimicrobial peptide synthesized in the liver [J]. J Biol Chem, 2001, 276(11): 7806～78l0.
[3] Hunter H N, Fulton D B, Ganz T, et a1. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis [J]. J Biol Chem, 2002, 277(40): 37597～37603.
[4] Ilyin G, Courselaud B, Troadec M B, et a1. Comparative analysis of mouse hepcidin 1 and 2 genes: evidence for different patterns of expression and coinducibility during iron overload [J]. FEBS Lett, 2003, 542(1-3): 22～26.
[5] Pigeon C, Ilyin G, Courselaud B, et a1. A new mouse liver specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload [J]. J Biol Chem, 2001, 276(11): 7811～7819.
[6] Nicolas G, Bennoun M, Devaux I, et a1. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2(USF2) Knockout Mice[J]. Proc Natl Acad Sci USA, 2001, 98(15): 8780～8785.
[7] Ganz T. Hepcidin: A peptide hormone at the interface of innate immunity and iron metabolism [J]. Curr Top Microbiol Immunol, 2006, 306: l83～l98.
[8] Nicolas G, Chauvet C,Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation [J]. J Clin Invest, 2002, 110(7): 1037～1044.
[9] Nemeth E, Tuttle M S, Powelson J, et a1. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization [J]. Science, 2004, 306(5704): 2090～2093.
[10] Detivaud L, Nemeth E, Boudjema K, et a1. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels and hepatic function [J]. Blood, 2005, 106(2): 746～748.
[11] Ganz T. Hepcidin: a regulator of intestinal iron absorption and iron recycling by macrophages [J]. Best Pract Res Clin Haematol, 2005, 18(2): 171～182.
[12] Yeh K Y, Yeh M, Glass J. Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat [J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286(3): 385～394.
[13] Frazer D M, Wilkins S J, Becker E M, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats [J]. Gastroenterology, 2002, 123(3): 835～844.
[14] Frazer D M, Anderson G J. The orchestration of body iron intake: how and where do enterocytes receive their cues? [J]. Blood Cells Mol Dis, 2003, 30(3): 288～297.
[15] Weinstein D A, Roy C N, Fleming M D, et a1. Inappropriate expression of hepcidin is associated with iron refractory anemia: implication for the anemia of chronic disease [J]. Blood, 2002, 100(10): 3776～3781.
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