Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin.
Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin.
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DOI：
10.1016/j.jcmgh.2018.06.006
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发表时间：
2018
影响因子：
7.2
通讯作者：
Anderson GJ
中科院分区：
文献类型：
--
作者：
Fuqua BK;Lu Y;Frazer DM;Darshan D;Wilkins SJ;Dunn L;Loguinov AV;Kogan SC;Matak P;Chen H;Dunaief JL;Vulpe CD;Anderson GJ
多铜铁氧化酶（MCFs）促进肠铁吸收和全身铁再循环，可能是通过涉及将来自铁输出体铁转运蛋白1的Fe 2+氧化以递送至循环Fe 3+载体转铁蛋白的机制。Hephaestin（HEPH）是已知在肠上皮细胞中表达的唯一MCF，有助于膳食铁向血液的基底外侧转移。在整个身体（Heph-/-）或肠道（Hephint/int）中缺乏HEPH的小鼠表现出膳食铁吸收的缺陷，但仍然存活和生长。循环铜蓝蛋白（CP）是已知的唯一可能与肠上皮细胞相互作用的MCF，我们的目的是评估HEPH和CP联合缺失对小鼠肠铁吸收和稳态的影响。产生缺乏HEPH和CP的小鼠（Heph-/-Cp-/-）和具有CP的全身敲除和HEPH的丝氨酸特异性缺失的小鼠（Hephint/intCp-/-）并进行表型分析。Heph-/-Cp-/-小鼠严重贫血，血清铁含量低，但它们在十二指肠肠上皮细胞、肝脏、心脏、胰腺和其他组织中表现出明显的铁负荷。Hephint/intCp-/-小鼠中度贫血（与Cp-/-小鼠相似），但仅在十二指肠和肝脏中负载铁，分别与Hephint/int和Cp-/-小鼠相同。在放射性标记的肠铁吸收研究中，两种双敲除模型都吸收了铁，但铁分布不适当，肝脏中保留的百分比异常高。这些研究表明，HEPH和CP，以及可能的MCFs一般来说，不是肠道铁吸收所必需的，但需要适当的全身铁分布。他们还指出了HEPH在维持全身铁稳态方面的重要肠外作用。
Multicopper ferroxidases (MCFs) facilitate intestinal iron absorption and systemic iron recycling, likely by a mechanism involving the oxidization of Fe2+ from the iron exporter ferroportin 1 for delivery to the circulating Fe3+ carrier transferrin. Hephaestin (HEPH), the only MCF known to be expressed in enterocytes, aids in the basolateral transfer of dietary iron to the blood. Mice lacking HEPH in the whole body (Heph-/-) or intestine alone (Hephint/int) exhibit defects in dietary iron absorption but still survive and grow. Circulating ceruloplasmin (CP) is the only other known MCF likely to interact with enterocytes. Our aim was to assess the effects of combined deletion of HEPH and CP on intestinal iron absorption and homeostasis in mice. Mice lacking both HEPH and CP (Heph-/-Cp-/-) and mice with whole-body knockout of CP and intestine-specific deletion of HEPH (Hephint/intCp-/-) were generated and phenotyped. Heph-/-Cp-/- mice were severely anemic and had low serum iron, but they exhibited marked iron loading in duodenal enterocytes, the liver, heart, pancreas, and other tissues. Hephint/intCp-/- mice were moderately anemic (similar to Cp-/- mice) but were iron loaded only in the duodenum and liver, as in Hephint/int and Cp-/- mice, respectively. Both double knockout models absorbed iron in radiolabeled intestinal iron absorption studies, but the iron was inappropriately distributed, with an abnormally high percentage retained in the liver. These studies indicate that HEPH and CP, and likely MCFs in general, are not essential for intestinal iron absorption but are required for proper systemic iron distribution. They also point to important extra-intestinal roles for HEPH in maintaining whole-body iron homeostasis.
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影响因子：
2.3
作者：
Cherukuri, S;Tripoulas, NA;Fox, PL
通讯作者：
Fox, PL
火铁黄蛋白和铜蓝蛋白促进小鼠肾脏中的铁代谢
影响因子：
4.6
作者：
Jiang B;Liu G;Zheng J;Chen M;Maimaitiming Z;Chen M;Liu S;Jiang R;Fuqua BK;Dunaief JL;Vulpe CD;Anderson GJ;Wang H;Chen H
通讯作者：
Chen H
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
DOI：
10.1016/j.jcmgh.2016.12.002
发表时间：
2017-05-01
影响因子：
7.2
作者：
Frazer, David M.;Wilkins, Sarah J.;Anderson, Gregory J.
通讯作者：
Anderson, Gregory J.
影响因子：
4.4
作者：
Hadziahmetovic, Majda;Dentchev, Tzvete;Dunaief, Joshua L.
通讯作者：
Dunaief, Joshua L.