Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis
The divalent metal ion transporter DMT1 is critical for nonheme iron import. We have previously shown that DMT1 is regulated in vitro by ubiquitination that is facilitated by the adaptor proteins Ndfip1 and Ndfip2. Here we report that in Ndfip1−/− mice fed a low- iron diet, DMT1 expression and activ...
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| Veröffentlicht in: | Blood 2011-01, Vol.117 (2), p.638-646 |
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| creator | Foot, Natalie J. Leong, Yew Ann Dorstyn, Loretta E. Dalton, Hazel E. Ho, Kristen Zhao, Lin Garrick, Michael D. Yang, Baoli Hiwase, Devendra Kumar, Sharad |
| description | The divalent metal ion transporter DMT1 is critical for nonheme iron import. We have previously shown that DMT1 is regulated in vitro by ubiquitination that is facilitated by the adaptor proteins Ndfip1 and Ndfip2. Here we report that in Ndfip1−/− mice fed a low- iron diet, DMT1 expression and activity in duodenal enterocytes are significant higher than in the wild-type animals. This correlates with an increase in serum iron levels and transferrin saturation. Liver and spleen iron stores were also increased in Ndfip1−/− mice fed a normal diet. Counterintuitive to the increase in iron uptake, Ndfip1−/− mice fed a low iron diet develop severe microcytic, hypochromic anemia. We demonstrate that this is due to a combination of iron deficiency and inflammatory disease in Ndfip1−/− mice, because Ndfip1−/−/Rag1−/− immunodeficient mice fed a low iron diet did not develop anemia and showed an iron overload phenotype. These data demonstrate that Ndfip1 is a critical mediator of DMT1 regulation in vivo, particularly under iron restricted conditions. |
| doi_str_mv | 10.1182/blood-2010-07-295287 |
| format | Article |
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We have previously shown that DMT1 is regulated in vitro by ubiquitination that is facilitated by the adaptor proteins Ndfip1 and Ndfip2. Here we report that in Ndfip1−/− mice fed a low- iron diet, DMT1 expression and activity in duodenal enterocytes are significant higher than in the wild-type animals. This correlates with an increase in serum iron levels and transferrin saturation. Liver and spleen iron stores were also increased in Ndfip1−/− mice fed a normal diet. Counterintuitive to the increase in iron uptake, Ndfip1−/− mice fed a low iron diet develop severe microcytic, hypochromic anemia. We demonstrate that this is due to a combination of iron deficiency and inflammatory disease in Ndfip1−/− mice, because Ndfip1−/−/Rag1−/− immunodeficient mice fed a low iron diet did not develop anemia and showed an iron overload phenotype. 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We have previously shown that DMT1 is regulated in vitro by ubiquitination that is facilitated by the adaptor proteins Ndfip1 and Ndfip2. Here we report that in Ndfip1−/− mice fed a low- iron diet, DMT1 expression and activity in duodenal enterocytes are significant higher than in the wild-type animals. This correlates with an increase in serum iron levels and transferrin saturation. Liver and spleen iron stores were also increased in Ndfip1−/− mice fed a normal diet. Counterintuitive to the increase in iron uptake, Ndfip1−/− mice fed a low iron diet develop severe microcytic, hypochromic anemia. We demonstrate that this is due to a combination of iron deficiency and inflammatory disease in Ndfip1−/− mice, because Ndfip1−/−/Rag1−/− immunodeficient mice fed a low iron diet did not develop anemia and showed an iron overload phenotype. These data demonstrate that Ndfip1 is a critical mediator of DMT1 regulation in vivo, particularly under iron restricted conditions.</description><subject>Anemia, Iron-Deficiency - etiology</subject><subject>Anemia, Iron-Deficiency - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Carrier Proteins - metabolism</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Homeostasis - physiology</subject><subject>Immunoblotting</subject><subject>Immunohistochemistry</subject><subject>Inflammation - metabolism</subject><subject>Intercellular Signaling Peptides and Proteins</subject><subject>Iron - metabolism</subject><subject>Iron, Dietary - metabolism</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microscopy, Confocal</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kLlOxDAQhi0EguV4A4TSICrD2HHWSYOEuCWOBmrLscdglMSLnUXi7fGyC3RUM8X3z_ERss_gmLGan7RdCJZyYEBBUt5UvJZrZMJypQAc1skEAKZUNJJtke2U3gCYKHm1SbY4NFUzBTEhNw_W-RmjFp03Hoex6L3B4lV_YOH7mfYRbXFx_8SKiC_zTo8-DIUebOFjbl5DjyGNOvm0Szac7hLureoOeb66fDq_oXeP17fnZ3fUVFCOlJsaS3BQtdqIumyYM1aA4NxZ65yYyqaVDrjQaBigwDY_aKaIxiG0tSzLHXK0nDuL4X2OaVS9Twa7Tg8Y5knVAsoq--GZFEvSxJBSRKdm0fc6fioGaqFQfStUC4UKpFoqzLGD1YJ526P9Df04y8DhCtDJ6M5FPRif_rhSCgGyztzpksOs48NjVGlh2KDNUs2obPD_X_IFMLuPbw</recordid><startdate>20110113</startdate><enddate>20110113</enddate><creator>Foot, Natalie J.</creator><creator>Leong, Yew Ann</creator><creator>Dorstyn, Loretta E.</creator><creator>Dalton, Hazel E.</creator><creator>Ho, Kristen</creator><creator>Zhao, Lin</creator><creator>Garrick, Michael D.</creator><creator>Yang, Baoli</creator><creator>Hiwase, Devendra</creator><creator>Kumar, Sharad</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20110113</creationdate><title>Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis</title><author>Foot, Natalie J. ; Leong, Yew Ann ; Dorstyn, Loretta E. ; Dalton, Hazel E. ; Ho, Kristen ; Zhao, Lin ; Garrick, Michael D. ; Yang, Baoli ; Hiwase, Devendra ; Kumar, Sharad</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c503t-2c8e30f05bac48391fcd40422fddff4679b7f024aec10e4eb201c6eecfe0b8733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Anemia, Iron-Deficiency - etiology</topic><topic>Anemia, Iron-Deficiency - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Carrier Proteins - metabolism</topic><topic>Cation Transport Proteins - metabolism</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Homeostasis - physiology</topic><topic>Immunoblotting</topic><topic>Immunohistochemistry</topic><topic>Inflammation - metabolism</topic><topic>Intercellular Signaling Peptides and Proteins</topic><topic>Iron - metabolism</topic><topic>Iron, Dietary - metabolism</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microscopy, Confocal</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Foot, Natalie J.</creatorcontrib><creatorcontrib>Leong, Yew Ann</creatorcontrib><creatorcontrib>Dorstyn, Loretta E.</creatorcontrib><creatorcontrib>Dalton, Hazel E.</creatorcontrib><creatorcontrib>Ho, Kristen</creatorcontrib><creatorcontrib>Zhao, Lin</creatorcontrib><creatorcontrib>Garrick, Michael D.</creatorcontrib><creatorcontrib>Yang, Baoli</creatorcontrib><creatorcontrib>Hiwase, Devendra</creatorcontrib><creatorcontrib>Kumar, Sharad</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Foot, Natalie J.</au><au>Leong, Yew Ann</au><au>Dorstyn, Loretta E.</au><au>Dalton, Hazel E.</au><au>Ho, Kristen</au><au>Zhao, Lin</au><au>Garrick, Michael D.</au><au>Yang, Baoli</au><au>Hiwase, Devendra</au><au>Kumar, Sharad</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2011-01-13</date><risdate>2011</risdate><volume>117</volume><issue>2</issue><spage>638</spage><epage>646</epage><pages>638-646</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>The divalent metal ion transporter DMT1 is critical for nonheme iron import. We have previously shown that DMT1 is regulated in vitro by ubiquitination that is facilitated by the adaptor proteins Ndfip1 and Ndfip2. Here we report that in Ndfip1−/− mice fed a low- iron diet, DMT1 expression and activity in duodenal enterocytes are significant higher than in the wild-type animals. This correlates with an increase in serum iron levels and transferrin saturation. Liver and spleen iron stores were also increased in Ndfip1−/− mice fed a normal diet. Counterintuitive to the increase in iron uptake, Ndfip1−/− mice fed a low iron diet develop severe microcytic, hypochromic anemia. We demonstrate that this is due to a combination of iron deficiency and inflammatory disease in Ndfip1−/− mice, because Ndfip1−/−/Rag1−/− immunodeficient mice fed a low iron diet did not develop anemia and showed an iron overload phenotype. 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| subjects | Anemia, Iron-Deficiency - etiology Anemia, Iron-Deficiency - metabolism Animals Biological and medical sciences Carrier Proteins - metabolism Cation Transport Proteins - metabolism Hematologic and hematopoietic diseases Homeostasis - physiology Immunoblotting Immunohistochemistry Inflammation - metabolism Intercellular Signaling Peptides and Proteins Iron - metabolism Iron, Dietary - metabolism Mass Spectrometry Medical sciences Membrane Proteins - metabolism Mice Mice, Knockout Microscopy, Confocal Reverse Transcriptase Polymerase Chain Reaction |
| title | Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis |
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