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1 Clinical Pediatric Hematology-Oncology Volume 25 ㆍ Number 1 ㆍ April 2018 REVIEW ARTICLE 철대사의이해 서진경ㆍ전인상 가천대학교의과대학소아과학교실 Jin Kyung Suh, M.D., Ph.D. and In-sang Jeon, M.D. Department of Pediatrics, College of Medicine, Gachon University, Incheon, Korea Iron is critical for almost all living organisms because it serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism. Disruption of iron homeostasis is associated with a wide range of diseases. Thus mammals have developed sophisticated mechanisms to maintain optimal range of iron concentration. Iron regulation involves processes at the systemic and cellular levels. These processes are regulated by hepcidin and iron regulatory proteins. Hepcidin modulates systemic iron homeostasis with ability to impede cellular iron export via interaction with the iron export protein, ferroportin. Whereas, iron regulatory proteins control cellular iron homeostasis by translational regulation of proteins which involve iron metabolism. Recent advances in the study of iron metabolism have shown promising results that hepcidin-targeted strategies may help to improve the diagnosis and treatment of iron related diseases. Although these strategies are now under development, ongoing studies can help to elucidate its application possibilities. Key Words: Iron metabolism, Iron metabolism disorders, Hepcidin pissn / eissn Clin Pediatr Hematol Oncol 2018;25:1 9 Received on March 26, 2018 Revised on April 3, 2018 Accepted on April 9, 2018 Corresponding Author: In-sang Jeon Department of Pediatrics, College of Medicine, Gachon University, 21 Namdongdaero 774 beongil, Namdong-gu, Incheon 21565, Korea Tel: Fax: isjeon@gilhospital.com ORCID ID: orcid.org/ 서론철은체내에서산소운반, 에너지생성, DNA 합성, 세포호흡에관여하는필수적인미량원소로서산소를운반하는중요한단백질인혈색소 (hemoglobin) 와근육조직에산소를공급하는미오글로빈 (myoglobin) 의주요구성성분으로작용한다. 이러한철의부족은철결핍빈혈과같은체내에필수적인철을보유한단백질의결핍을유발하고, 과잉공급된철은활성화산소를생성하는화학반응의촉매역할을함으로써조직을손상시켜질병을유발하는것으로알려져있다. 따라서, 적정농도의철을유지하기위해전신 (systemic) 및세포 (cellular) 단계에서여러가지복잡한기전을통해철의대사가이루어지고있다. 이러한철대사에관련된연구는끊임없이이어지고있어매년수천개의관련논문들이보고되고있는것으로알려져있으며, 특히최근 10년동안에는관련된핵심기전과중요한역할을하는단백질들이밝혀져철관련질병들의병인과치료를이해하는데도움을주고있어본논문을통해이를살펴보고자한다. 전신에서의철의대사정상성인의경우체내에약 3-5 g의철을보유하고있는것으로알려져있으며, 이중대략 60% 는혈색소에, 10% 정도 1

2 Jin Kyung Suh and In-sang Jeon 가미오글로빈에포함되어있고나머지 30% 는간세포 (hepatocyte) 와망상내피계대식세포 (reticuloendothelial macrophage) 에저장되어있는것으로알려져있다. 정상성인의체내에서는매일이천억개이상의적혈구가생성되고여기에는 mg의철이필요한데대부분이망상내피계대식세포에저장되어있던노쇠한적혈구에서유래된철이재활용되고 1-2 mg 정도의철이십이지장의소장상피세포를통해흡수되어소장상피세포의탈락, 땀, 출혈등으로소실되는양을보충하고있다. 전신적단계에서철의항상성을유지하는데는세포밖으로철을배출하는수송체인 ferroportin (FPN) 과이를조절하는호르몬인 hepcidin이일차적으로관여한다 (Fig. 1). 1) 철의흡수체내로유입되는철은식품을통해서만섭취되며헴철 (heme iron) 과비헴철 (nonheme iron) 로나뉜다 [1]. 비헴철은동식물성식품모두에, 특히식물성식품에많이포함되어있는철로서헴단백질외의다양한단백질에결합되어존재하지만, 비교적결합력이떨어져서주위환경의영향을많이받 는것으로알려져있다. 예를들면, 위와소장의낮은 ph 환경, 시트러스산과아스코르브스산은철을환원시켜용해성을유지할수있게함으로써흡수력을향상시키고, 탄닌산 (tannin), 피테이트산 (phytate), 폴리페놀 (polyphenol) 등의성분은비헴철과결합해서흡수를방해한다. 반면, 주로미오글로빈이나혈색소에포함이되어있어동물성식품에서유래하는것으로알려진헴철은 protoporphyrin ring에단단히결합되어있어서흡수에있어서다른요소들의영향을받지않는다 [2]. 식품으로섭취된철은소장의근위부, 즉십이지장과공장의장세포에의해흡수되는것으로알려져있다. 식품에포함된철은대부분 3가철 (ferric iron, Fe 3+ ) 형태로존재하는데, 장세포에존재하는십이지장시토크롬 B (dudodenal cytochrome B, DcytB) 에의해환원되어세포내에서수송가능한형태인 2가철 (ferrous iron, Fe 2+ ) 로바뀐후에수송체인 divalent metal transporter 1 (DMT1) 에의해흡수된다 [3,4]. 흡수된철은철수송단백질인 FPN에의해세포밖으로배출되어혈장으로옮겨지게되고혈장에서는두개의 3가철결합부위를가진트랜스페린 (transferrin, Tf) 에결합되어혈장내에서 Fig. 1. Systemic iron metabolism: adapted from reference [2] and [36]. Duodenal enterocyte absorbs dietary iron via DMT1 on the apical brush-border membrane after reduction of Fe 3+ to Fe 2+ through duodenal cytochrome B (DcytB). Reticuloendothelial macrophages in spleen recyle iron from senescent erythrocytes. Each cells export iron via ferroportin (FPN) with the aid of hephaestin, which converts newly transported Fe 2+ to Fe 3+. Iron oxidization also performs by ceruloplasmin in the circulation. In the plasma, transferrin (Tf) captures iron and transports it to the organs which utilize iron. Hepcidin, the key regulator of systemic iron homeostasis, affects iron efflux from cells by regulating the stability of FPN. Synthesis and secretion of hepcidin by hepatocytes is influenced by iron levels as well as conditions that affect iron metabolism indirectly such as inflammation, ER stress, erytheopoiesis, and hypoxia. Holo-Tf, diferric-transferrin complex; HOX1, heme oxygenase 1. 2 Vol. 25, No. 1, April 2018

3 체내를순환하면서철이필요한조직에운반되는데, 장세포에서혈장으로배출되는과정에는철산화효소인 hephaestin (HEPH) 에의해 2가철이다시 3가철로산화되는과정이필요하다 [5-8]. 반면, 사용되지않고장세포내에남아있는철은페리틴 (ferritin) 에저장되어수일이내장상피세포의탈락과함께사라지게된다. 이러한흡수기전은주로비헴철에관한것으로헴철의흡수기전에대해서는아직까지밝혀진것이많지않다. 단지세포내섭취 (endocytosis) 와같은어떤기전에의해장세포내로들어오면헴산화효소 (heme oxygenase 1, HO1) 에의해산화되면서세포내로유리되고비헴철과같은기전으로체내에서필요한조직으로수송될것이라고추측되고있을뿐이다 [9,10]. 2) 트랜스페린앞서설명했듯이혈장내로유리된철은트랜스페린에결합되어철을필요로하는조직으로이동한다 [11]. 혈장에존재하는대부분의철은트랜스페린에결합되어있는것으로알려져있는데, 이러한기능을통해철을이동시킬뿐아니라트랜스페린에결합되지않은철 (non-transferrin-bound-iron, NTBI) 이형성하는독성유리기 (toxic radical) 의생성을제한하는역할을한다 [12]. 철과결합되어있는트랜스페린의농도인트랜스페린의포화도 (transferring saturation, TSAT) 는조직으로의원활한철공급을반영하는지표가되는데, 알려진바로는건강한사람에서약 30% 의트랜스페린이철과결합되어있고, 16% 이하의트랜스페린포화도는적혈구생성이감소되어있음을나타낸다 [13]. 3) 철의이용과저장혈장내에서순환하는철-트랜스페린복합체 (holo-tf) 는세포표면에있는트랜스페린수용체 1 (transferrin receptor 1, TfR1) 와결합해서엔도솜 (endosome) 을형성하여세포내로유입되고엔도솜내에서 STEAP (six transmembrane epithelial antigen of the prostate) 단백에의해 3가철이 2가철로환원되면서트랜스페린으로부터철이유리되어엔도솜막의 DMT1을통해세포질로방출된다 [11,14,15]. 이중대사에이용될철은미토콘드리아로유입되어단백질합성에쓰여지고사용되지않고남아있는철은페리틴에저장된다. 세포내에철이과잉공급되면 FPN을통해세포밖으로유출되는데, 장세포에서는 hephaestin이 2가철을 3가철로산화시켰다면, 다른조직들에서는 ceruloplasmin이여기에관여하는것으로알려져있다 [16]. 체내여러기관에서철을필요로하지만, 적혈구를생성하는골수에서는가장많은양의철을필요로하고, 대부분은대식세포 (macrophage), 특히비장의대식세포에의해체내에서재활용되는철로충족되는것으로알려져있다. 대식세포는노쇠한적혈구를포획하여헴산화효소로분해함으로써철을유리시킨후페리틴에저장해두었다가체내에서철필요도가증가하면 FPN을통해혈장으로배출한다 [12,17,18]. 또한, 간세포에서는세포내로유입된대부분의철이페리틴에저장되는데, 특히혈중철농도가트랜스페린의결합범위를넘어서게되면, NTBI의주된저장소가된다 [17]. 이러한철과잉상태에서 NTBI의주된저장소가되는기관으로는간외에도심장과췌장이있고, NTBI가세포내로유입되는기전에대해서는확실하게알려지지는않았지만, 아연수송체인 Zip/Irt-like protein 14 (Zip14) 가관여하는것으로알려져있다 [19]. 한편, 간세포에는두종류의트랜스페린수용체가존재하는데, 트랜스페린수용체 1 (TfR1) 은 holo-tf와결합하는역할을하고트랜스페린수용체 2 (TfR2) 는주로트랜스페린포화도의감지기역할을하고상대적으로 holo-tf에대한결합력은떨어지는것으로알려져있다 [20-22]. 4) 전신에서철의항상성유지 Hepcidin은전신의철항상성을유지하는데가장중요한역할을하는물질이다. 이물질은주로간에서합성되며장세포와대식세포, 그리고간세포등에서철이혈장으로유리되는것을방해하는역할을함으로써혈중철의농도와트랜스페린포화도를조절한다 [23,24]. 이는 hepcidin이철을세포밖으로배출하는운반체인 FPN에결합하여용해소체 (lysosome) 를형성함으로써철을제거하는기능을가지고있기때문인데, 이기능은 Janus kinase 2 (JAK2) 가 hepcidin- FPN 결합체에붙어서 FPN을인산화 (phosphorylation) 시킴으로써가능해지는것으로밝혀졌다 [25,26]. 따라서, 체내에서철이과잉상태인경우에는 hepcidin의혈중농도는올라가게되고, 철이부족한상태인경우에는 hepcidin의혈중농도는내려가게된다. 5) Hepcidin 유전자의전사조절 Hepcidin은주로혈중철의농도에반응하여전사단계에서합성이조절되는데, 혈중철의농도외에도염증반응에의한물질들 (inflammatory cytokines) 과저산소상태와같은요소들에의해서도영향을받는것으로알려져있고여기에관련된몇가지신호전달체계 (signaling pathway) 가밝혀져있다 (Fig. 2). Clin Pediatr Hematol Oncol 3

4 Jin Kyung Suh and In-sang Jeon Fig. 2. Cellular iron metabolism and transcriptional regulation of hepcidin: adapted from reference [2], [10], and [36]. Cells uptake iron from holo-tf via transferin receptor 1 (TfR1) on the cell surface. The complex of holo-tf and TfR1 undergoes endocytosis, which is accompanied by iron reduction by 6-transmembrane epithelial antigen of the prostate (STEAP3). Newly acquired iron enters into cytosolic labile iron pool (LIP), which is redox-active. LIP is attached to poly(rc)-binding protein (PCBP) and delivered to the iron storage protein, ferritin or mitochondria to synthesize iron-containing proteins. Cellular iron that is not utilized is either stored in ferritin or exported via FPN. Heme iron is exported via feline leukemia virus subgroup C cellular receptor (FLVCR) or ATP binding cassette protein G2 (ABCG2). BMP6, bone morphogenic protein 6; BMP-R, BMP receptor; DMT1, divalent metal transporter 1; FPN, ferroportin; HFE, hephaestin; HJV, hemojuvelin; Holo-Tf, diferric-transferrin complex; NEO1, neogenin 1; NTBI, non-transferrinbound-iron; TMPRSS6, transmembrane serine protease 6; Zip14, Zip/Irt-like protein 14. 가장중요한것은전사인자인 bone morphogenetic protein (BMP) 과관련된기전으로, BMP6가핵심적인역할을하는것으로알려져있다 [27,28]. BMP는수용체 (BMP-R) 와보조수용체 (co receptor) 인 hemojuvelin (HJV) 에결합하여 R-SMAD 단백을인산화시킴으로써관련전사복합체를활성화시켜 BMP가 hepcidin 유전자의촉진자 (promoter) 에결합하여 hepcidin의합성을촉진시킬수있도록한다 [27,29]. 이과정은 neogenin (NEO1) 과 transmembrane serine protease 6 (TMPRSS6) 에의해조절되는데, NEO1은 HJV를안정화함으로써 hepcidin의발현을촉진시키고, TMPRSS6는 HJV를분절시킴으로써 hepcidin의합성을방해하는것으로알려져있다 [30,31]. 그외에도 hemochromatosis proteins (HFEs) 와관련된기전도 hepcidin의발현을조절하는것으로알려져있다. HFE 는 3가철-트랜스페린복합체와트랜스페린수용체인 TfR1, TfR2의결합에영향을미치는데, 3가철-트랜스페린복합체의 농도가높은환경에서는이복합체들이 TfR1으로부터유리되어 TfR2와결합하게되고 HFE-TfR2 복합체는 hepcidin 유전자의전사를촉진하게된다 [32,33]. 또한, 염증반응에관련되는물질들중 interleukin-6 (IL-6) 도 signal transducer and activator of transcription 3 (STAT3) 를활성화하여 STAT3가 hepcidin 유전자의촉진자에결합하는것을유도하는것으로알려져있는데, 이기전은만성감염과급성염증반응및암질환에서저페리틴혈증 (hypoferritinemia) 이동반되는것에대한근거가된다 [34,35]. 세포내에서의철의대사 DMT1을통해세포내로유입된철은이가철형태로존재하게되는데, 이를자유철 (free iron) 이라고하며이들세포자유철들의집단을 labile iron pool (LIP) 라고한다 [10,36]. 자유철은유독한수산화기 (hydroxyl radical) 를형성하므로세포 4 Vol. 25, No. 1, April 2018

5 내에서는이러한자유철을샤페론 (chaperone) 이나단백질에결합시켜두는방식으로자유철을보유하게되는데, 잘알려진것이 poly(rc)-binding protein (PCBP) 와페리틴이다 [37]. PCBP 는최근에밝혀진세포내에존재하는철결합샤페론으로아직기전이명확히밝혀지지는않았으나철을페리틴이나몇몇효소들에전달하는역할을하고페리틴은앞서설명한바와같이세포내철의저장에가장중요한역할을하는단백으로, 최대 4,500개의철원자를저장할수있어세포내철농도가증가하면막강한능력을발휘하여철과결합함으로써자유철이세포를손상시키는것을막는다 [38]. 소량의페리틴은세포밖으로유리되어혈장에서존재하게되는데, 이농도는세포내철의농도와밀접하게연관되어있어혈중페리틴의농도는체내에저장된철의양을시사하는지표가된다. 한편, 철과결합된페리틴의농도가높아지면페리틴분자들은서로결합하여용해소체를형성하게되고헤모시데린 (hemosiderin) 이라고알려진 3가철-펩티드 (peptide) 결합체로분해되는데, 이헤모시데린은철과잉과관련된질환에서가장많이관찰되는세포형태이다 [38]. 1) 세포내에서철의유입과배출전신에서의철의흡수에서살펴본바와같이세포내로철이유입되는데는주로두가지기전이이용된다. 대부분의세포에서는 TfR1을세포막표면에가지고있어서혈장에존재 하는 3가철-트랜스페린복합체가 TfR1에결합하면서세포내섭취 (endocytosis) 된후 STEAP에의해 3가철이 2가철로환원되어트랜스페린으로부터유리되는기전으로철의유입이이루어지는것으로알려져있는데, 장세포와같은몇몇특이한세포에서는 DMT1이라는수송체가세포막에존재하여세포밖에존재하는 2가철을세포내로유입시킨다. 그외에도 Zip14를통해서 NTBI가, heme carrier protein 1에의해헴철이세포내로유입되는것으로알려져있다 [15,19,39]. 반면, 세포밖으로철을배출하는데이용되는기전은알려진바가많지않아서 2가철수송체로서는 FPN이유일하고헴철의수송체로는 feline leukemia virus subgroup C cellular receptor (FLVCR) 와 ATP binding cassette protein G2 (ABCG2) 가있어과잉된헴철을세포밖으로배출한다 (Fig. 2) [40,41]. 2) 세포내에서철의항상성유지철의양을일정하게유지하기위해서세포내에서는 iron regulatory protein (IRP) 과 iron responsive element (IRE) 가작용한다. IRP는철의대사와관련되는단백을합성하는 messenger RNA (mrna) 의 untranslated region (UTR) 에존재하는 IRE에결합하여철대사관련단백의합성을조절하는것으로알려져있는데, 직접 IRE에결합하여조절능력을발휘하는 IRP1과철분과잉일때만활성화되어분해과정에작용하는 IRP2로분류된다 [42,43]. 한편, IRE는페리틴과 FPN을합성하 Fig. 3. Intracellular iron regulation: adapted from reference [10] and [43]. The iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. IRP1 and IRP2 interact by binding to IRE, cis-regulatory hairpin structures that are present in the untranslated regions (UTRs) of mrnas involved in iron metabolism. Binding of IRP s to 5 UTR IREs inhibits the translation of ferritin and ferroportin (FPN), while binding to the 3 UTR IREs results in the stabilization of mrna of the iron importer TfR1 with increasing iron levels. Cellular iron loading converts IRP1 from IRE-binding form to an Fe-S cluster and triggers proteasomal degradation of IRP2. DMT1, divalent metal transporter 2; TfR1, transferrin receptor 1. Clin Pediatr Hematol Oncol 5

6 Jin Kyung Suh and In-sang Jeon 는 mrna에서는 5'UTR에한개가존재하고, TfR1을합성하는 mrna에서는 3'UTR에여러개가, 그리고 DMT1을합성하는 mrna에서는 3'UTR에한개가존재하는것으로알려져있는데, 세포내에철이부족한상태에서는 IRP가 5'URT에존재하는 IRE와결합하여 mrna의전사를방해함으로써페리틴과 FPN의합성을감소시키고, 3'URT에존재하는 IRE와결합하여 TfR1과 DMT1의합성을증가시켜세포내로철의유입을증가시키는것으로알려져있다. 반면에, 세포내에철이과잉상태가되면, IRP는 iron sulfur 집합체 (cluster) 로불활성화되어 IRE와결합하지않게되고 IRP는 proteasomal degradation 에관여하게된다 (Fig. 3) [43]. 철의대사와관련된질병선천적으로또는후천적으로철대사관련단백의유전자에변이가생기거나, 식품으로섭취한철의양이부적절했거나, 적혈구수혈했거나, 철분주사제를맞았거나출혈이있었거나, 또는용혈이발생했거나다양한원인들로인해체내의철의항상성이깨지게되면질병이발생한다. 철이과잉인경우, 철이부족한경우발생할수있는질병을살펴보면다음과같다 (Table 1). 1) 철의부족철결핍증은빈혈의가장흔한원인이다. 체내철의삼분의이이상은혈색소를합성하는데쓰여진다. 따라서철의양이부족하게되면적혈구형성에영향을주게된다. 철부족으로 인해발생하는질병에는철결핍빈혈과만성염증에의한빈혈 (anemia of chronic inflammation) 이있다. 철결핍빈혈은대부분경구철분제 (ferrous sulfate, ferrous gluconate, ferrous fumarate) 로부족한철을보충해주면교정이되는데, 일부심한철결핍빈혈에서는정맥주사제가필요한경우도있다 [44]. 드물게는 hepcidin의작용을방해하는단백질인 TMPRSS6의유전자에변이가생겨 hepcidin이과하게작용함으로써철분제치료에반응하지않는빈혈 (iron-refractory iron-deficiency anemia, IRIDA) 이발생하기도한다 [45]. 또한, 종양이나만성감염, 염증질환, 기타외상이나다발성장기부전과같은스트레스상황등에서는체내에 IL-6가증가하면서 STAT3를활성화시켜 hepcidin이과잉생성되므로혈중철의농도가감소하고혈색소생성이저하되어빈혈이발생하기도하는데, 이를만성염증에서의빈혈이라고한다 [35,46]. 2) 철의과잉철이과잉상태가되면간, 심장, 췌장과같은주요장기에 NTBI 형태의철이축적되게되는데, 이러한 NTBI는앞서언급했듯이수산화기또는지질기 (lipid radical) 을생성함으로써조직을손상시켜간경화, 종양, 관절염, 부정맥, 심부전, 망막변성, 당뇨, 각종신경퇴행성질환을일으키는위험인자로작용하는것으로알려져있다. 이렇게체내에철분이축적되게하는원인은크게두가지로분류할수있는데, 철의대사에관련된물질들의유전자변이에의한일차성철과잉과잦은수혈에의해발생하는이차성철과잉이있고그치료로는사혈 (phlebotomy) 와철킬레이트화치료 (iron chelating ther- Table 1. Genes involved in iron-related disorders [10] Disorder Genes Protein Protein function Hemochromatosis Hephaestin Hephaestin Involved in transcriptional regulation of hepcidin Hemochromatosis TfR2 Transferrin receptor 2 Holo-Tf sensor; at high Tf levels, HFE interaction with TfR2 is increased promoting hepcidin expression Juvenile hemochromatosis HJV Hemojuvelin Involved in transcriptional regulation of hepcidin; BMP co-receptor Juvenile hemochromatosis HAMP Hepcidin Modulates serum iron levels; regulates iron efflux by binding to the iron exporter ferroportin, triggering its internalization and degradation Homechromatosis SLC40A1 Ferroportin Iron exporter (hepcidin resistance) Aceruloplasminemia CP Ceruloplasmin Ferroxidase Hypotransferrinemia TF Transferrin Glycoprotein with two binding sites for ferric iron IRIDA TMPRSS6 Matriptase-2 Cleaves HJV, Inactivates it and, consequently, inhibits production of hepcidin BMP, bone morphogenic protein; HFE, hephaestin; IRIDA, iron-refractory iron-deficiency anemia; TfR, transferrin receptor; TMPRSS6, transmembrane serine protease 6. 6 Vol. 25, No. 1, April 2018

7 apy) 가있는데, 철과잉원인에따라치료가달라진다 [47]. (1) 일차성철과잉일차성철과잉은대부분유전성혈색소증 (hereditary hemochromatosis) 에의한것으로, 변이된유전자의종류에따라 HFE에변이가있는 1형, HJV에있는 2A형, hepcidin에변이가있는 2B형, TfR2에변이가있는 3형, 마지막으로 FPN 에변이가있는 4형의다섯가지형태로분류된다 [48]. 1형부터 3형까지는 hepcidin 부족을 4형은 hepcidin의활성을떨어뜨리므로써철의과잉이유발되고철의축적으로간섬유화와간경화, 악성간세포종, 심근염, 관절염, 당뇨의위험도가증가하는것이특징이다. 유전성혈색소증외에도 ceruloplasmin 유전자의결함에의한 aceruloplasminemia, 트랜스페린부족에의한 hypotransferrinemia/atransferrinemia도일차성철과잉을유발한다. 이들일차성철과잉의치료로는사혈 (phlebotomy) 이주로사용되는데, 혈액 1 L당 0.5 g의철을제거하면서축적된철이새로운적혈구를형성하는데쓰이도록유도하게되므로매우효과적이면서도비교적경제적부담이적은것으로알려져있다 [49]. (2) 이차성철과잉우리가적혈구수혈시에사용하는혈액제제 1 unit에는 mg의철이포함되어있는데, 이는하루필요량 (1-2 mg) 의 100배에해당하는양으로, 탈라세미아, 낫세포빈혈과같은유전용혈빈혈환자, 골수부전증환자, 그리고항암치료중인환자들은지속적인적혈구수혈로인한이차성철과잉이발생할위험이높다. 이렇게이차성으로발생한철과잉의치료로서사혈은도움이되지않고 deferoxamin 또는 deferasirox와같은철킬레이트제제를쓰는것이효과적인것으로알려져있다 [47]. Hepcidin과관련된새로운진단법과치료앞서살펴본바와같이 hepcidin은철과관련된질환들에서핵심적인역할을하고있으므로새로운진단법이나치료법개발에이용가치가있다. 이와관련된연구들이활발히진행되고있는데, 현재까지연구된결과를살펴보면다음과같다 (Table 2). 1) Hepcidin 분석법 (assays) Hepcidin은면역분석법 (immunoassay) 과질량분석법 (mass spectrometry) 으로혈청, 혈장, 그리고소변에존재하는양을측정할수있는데, ELISA와같은면역분석법이더효율적인것으로알려져있으며, 한임상연구에서는 ELISA법으로측정한혈청 hepcidin 농도를만성염증에의한빈혈과철겹핍빈혈을가진환자군에서각각측정하여비교한결과유의한차이를보여이들질환을감별진단하는생체지표로서활용가치가있다고보고한바가있다 [50,51]. 그러나, 이러한면역분석법은전체 hepcidin의양을측정하므로활성도높은 full-length hepcidin과활성도가떨어지는 smaller isoform을구별해서측정할수는없고, 각각의 isoform을구별해서측정하는것이철관련질환의진단에도움을주는지는불분명하여실제로진단에이용되는데는한계가있다는것이현재까지의결론이다 [52]. 한편, 소변에존재하는 hepcidin의양은혈청, 혈장내에존재하는양을잘반영하므로 hepcidin 분석에이용이가능하지만, 여기에는 smaller isoform이많고측정치의변이폭이넓으며사구체여과율과같은신기능의영향을받는다는한계가있는것으로알려져있다. 이러한한계들 Table 2. Hepcidin-targeting therapeutic approaches [53] Therapeutic approach Targeted disease Mode of action Agents Hepcidin agonists Hepcidin antagonists Iron overload (hereditary hemochromatosis and iron-loading anemias) Iron-restricted anemias (anemia of inflammation, anemia of chronic kidney disease, anemia of cancer, IRIDA) Hepcidin mimics Stimulators of hepcidin production Suppressors of hepcidin production Hepcidin peptide neutralizing binders Agents interfering with hepcidin-ferroportin interaction Minihepcidins Gene silencing of TMPRSS6 BMP pathway inhibitors Anti-inflammatory agents Erythropoiesis-stimulating agents Gene silencing of hepcidin and its regulators Antihepcidin antibodies Anticalins Spiegelmers Antiferroportin antibodies Thiol modifiers BMP, bone morphogenic protein; IRIDA, iron-refractory iron-deficiency anemia; TMPRSS6, transmembrane serine protease 6. Clin Pediatr Hematol Oncol 7

8 Jin Kyung Suh and In-sang Jeon 로 hepcidin 분석은실험적으로만이용되고있으나, 측정치를표준화할수있는방법이개발되어한계점들을보완한다면, 철관련질환을진단하는데효과적으로이용될수있을것이라여겨진다 [53]. 2) Hepcidin 작용제 (agonist) 유전성혈색소증과같이 hepcidin의부족으로철과잉상태가되는질환에는 hepcidin과유사하게작용하는 hepcidin 작용제나 hepcidin의생성을촉진하는물질을투여함으로써치료효과를얻을수있다. 천연 hepcidin 은분자량이크고여러번접혀있는모양으로존재하는데다반감기가짧아서이를합성하는것은상대적으로효율성이떨어지므로 minihepcidin 이라는 hepcidin 작용제를고안하였는데, 이는 hepcidin에서 FPN와작용하는부위를위주로합성하여분자량을줄이고생체이용률 (bioavailability) 과반감기를향상시킨물질이다 [54]. Hepcidin의합성을촉진하는물질로서, TMPRSS6의 RNA에결합하여합성을방해하는물질이개발되어동물실험에서효과가입증되었다 [53]. 3) Hepcidin 대항제 (antagonist) 혈중 hepcidin의증가는만성염증에서의빈혈, TMPRSS6 유전자변이에의한철분제에반응하지않는빈혈을유발하는것으로알려져있는데, 이런경우에는 hepcidin 대항제가치료에효과적일수있다. 현재까지개발된대항제들은 BMP 신호전달체계에작용해서 hepcidin의합성을방해하거나 FPN 항체의형태로 hepcidin이 FPN에결합하는것을방해하거나 hepcidin에대한중화항체형태로 hepcidin을중화시키는방법으로작용하게된다 [54]. 대부분의대항제들은전임상동물연구에서효과가입증되었고일부임상연구에서도효과가확인된바가있다 [53]. 결론철은체내에서중요한역할을하는동시에잠정적인독성을가지고있어항상성이유지되지않으면각종질병을유발한다. 따라서철의대사에대한연구는끊임없이이어지고있으며, 아직밝혀지지않은기전도많지만 hepcidin과 FPN의상호작용을주축으로전신의철의항상성이유지되는기전과 IRP-IRE에의한세포내에서의철의대사조절기전을밝혀내므로써큰발전을이루었다고할수있다. 특히 hepcidin의발견은괄목할만한성과로그노력이 hepcidin을이용한새로운진단법과표적치료제의개발까지이어져기존에철관 련질환들에사용되고있던진단과치료법의발전가능성을열어주고있다. References 1. Ganz T. Systemic iron homeostasis. Physiol Rev 2013;93: Anderson GJ, Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr 2017;106(Suppl 6):1559s-66s. 3. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005;115: McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 2001;291: Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000;275: Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000;403: Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999;21: Schade AL, Caroline L. An iron-binding component in human blood plasma. Science 1946;104: Ferris CD, Jaffrey SR, Sawa A, et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol 1999;1: Chifman J, Laubenbacher R, Torti SV. A systems biology approach to iron metabolism. Adv Exp Med Biol 2014;844: Frazer DM, Anderson GJ. The regulation of iron transport. Biofactors 2014;40: Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell 2010;142: Bainton DF, Finch CA. The diagnosis of iron deficiency anemia. Am J Med 1964;37: Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 2005;37: Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood 2006;108: Sharp P. The molecular basis of copper and iron interactions. Proc Nutr Soc 2004;63: Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol 2007;69: Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/slc40a1 is essential for iron homeostasis. Cell Metab 2005;1: Vol. 25, No. 1, April 2018

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