Fuqua Brie K, Lu Yan, Darshan Deepak, Frazer David M, Wilkins Sarah J, Wolkow Natalie, Bell Austin G, Hsu JoAnn, Yu Catherine C, Chen Huijun, Dunaief Joshua L, Anderson Gregory J, Vulpe Chris D
Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, United States of America; Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
PLoS One. 2014 Jun 4;9(6):e98792. doi: 10.1371/journal.pone.0098792. eCollection 2014.
Hephaestin is a vertebrate multicopper ferroxidase important for the transfer of dietary iron from intestinal cells to the blood. Hephaestin is mutated in the sex-linked anemia mouse, resulting in iron deficiency. However, sex-linked anemia mice still retain some hephaestin ferroxidase activity. They survive, breed, and their anemia improves with age. To gain a better understanding of the role of hephaestin in iron homeostasis, we used the Cre-lox system to generate knockout mouse models with whole body or intestine-specific (Villin promoter) ablation of hephaestin. Both types of mice were viable, indicating that hephaestin is not essential and that other mechanisms, multicopper ferroxidase-dependent or not, must compensate for hephaestin deficiency. The knockout strains, however, both developed a microcytic, hypochromic anemia, suggesting severe iron deficiency and confirming that hephaestin plays an important role in body iron acquisition. Consistent with this, the knockout mice accumulated iron in duodenal enterocytes and had reduced intestinal iron absorption. In addition, the similarities of the phenotypes of the whole body and intestine-specific hephaestin knockout mice clarify the important role of hephaestin specifically in intestinal enterocytes in maintaining whole body iron homeostasis. These mouse models will serve as valuable tools to study the role of hephaestin and associated proteins in iron transport in the small intestine and other tissues.
血浆铜蓝蛋白氧化酶是一种脊椎动物多铜铁氧化酶，对膳食铁从肠道细胞向血液的转运至关重要。血浆铜蓝蛋白氧化酶在性连锁贫血小鼠中发生突变，导致缺铁。然而，性连锁贫血小鼠仍保留一些血浆铜蓝蛋白氧化酶活性。它们能够存活、繁殖，并且贫血状况会随着年龄增长而改善。为了更好地理解血浆铜蓝蛋白氧化酶在铁稳态中的作用，我们使用Cre-lox系统构建了全身或肠道特异性（绒毛蛋白启动子）血浆铜蓝蛋白氧化酶缺失的基因敲除小鼠模型。这两种类型的小鼠都能存活，表明血浆铜蓝蛋白氧化酶并非必不可少，并且其他机制，无论是否依赖多铜铁氧化酶，都必须补偿血浆铜蓝蛋白氧化酶的缺乏。然而，这两种基因敲除品系都出现了小细胞低色素性贫血，提示严重缺铁，并证实血浆铜蓝蛋白氧化酶在机体铁摄取中起重要作用。与此一致的是，基因敲除小鼠在十二指肠肠细胞中积累了铁，并且肠道铁吸收减少。此外，全身和肠道特异性血浆铜蓝蛋白氧化酶基因敲除小鼠的表型相似性，阐明了血浆铜蓝蛋白氧化酶在肠道肠细胞中对维持全身铁稳态的重要作用。这些小鼠模型将成为研究血浆铜蓝蛋白氧化酶及相关蛋白在小肠和其他组织中铁转运作用的有价值工具。
