Zoller Heinz, Theurl Igor, Koch Robert O, McKie Andrew T, Vogel Wolfgang, Weiss Gü
Department of Medicine, University Hospital of Innsbruck, Innsbruck, Austria.
Gastroenterology. 2003 Sep;125(3):746-54. doi: 10.1016/s0016-5085(03)01063-1.
BACKGROUND & AIMS: An increased duodenal expression of the iron transporters, divalent-metal-transporter-1, and ferroportin is observed in patients with iron deficiency or hereditary hemochromatosis. Two oxidoreductases, termed duodenal cytochrome b and hephaestin, are proposed to co-operate with divalent-metal-transporter-1 and FPN1, respectively, to transfer iron from the duodenal lumen to the circulation.
In the present study, we investigated the mRNA and protein expression of Dcytb and hephaestin in duodenal biopsies from patients with iron deficiency, HFE, and non-HFE-associated hemochromatosis and in control subjects by means of real-time polymerase chain reaction, Western blot, and immunofluorescence.
In iron deficiency a coordinated upregulation of the iron transporters divalent-metal-transporter-1 and ferroportin and of duodenal-cytochrome b and hephaestin was found, whereas in patients with HFE and non-HFE-associated hemochromatosis duodenal-cytochrome b and hephaestin protein and mRNA expression were not significantly different from control subjects. However, HFE but not non-HFE hemochromatosis patients presented with an increased duodenal ferric reductase activity. Spearman rank correlations showed that Dcytb, hephaestin, FPN1, and DMT1 mRNA expression are positively related to each other independently of the underlying disease, which ensures an efficient transepithelial transport of absorbed iron.
Our data show that duodenal-cytochrome b activity in iron deficiency is stimulated via enhanced protein expression, whereas in HFE hemochromatosis it is up-regulated post-translationally. This points to different kinetics of intestinal iron uptake between iron deficiency and HFE hemochromatosis and also indicates that duodenal iron accumulation in HFE and non-HFE hemochromatosis is pathophysiologically different.
在缺铁性贫血或遗传性血色素沉着症患者中，十二指肠中铁转运蛋白二价金属转运体1（divalent-metal-transporter-1，DMT1）和铁转运蛋白（ferroportin）的表达增加。两种氧化还原酶，即十二指肠细胞色素b（duodenal cytochrome b，Dcytb）和亚铁氧化酶（hephaestin），分别被认为与DMT1和FPN1协同作用，将铁从十二指肠腔转运至血液循环。
在本研究中，我们通过实时聚合酶链反应、蛋白质印迹法和免疫荧光法，调查了缺铁性贫血、HFE和非HFE相关血色素沉着症患者以及对照受试者十二指肠活检组织中Dcytb和hephaestin的mRNA和蛋白质表达。
在缺铁性贫血中，发现铁转运蛋白DMT1和铁转运蛋白以及十二指肠细胞色素b和亚铁氧化酶的表达协同上调，而在HFE和非HFE相关血色素沉着症患者中，十二指肠细胞色素b和亚铁氧化酶的蛋白质及mRNA表达与对照受试者无显著差异。然而，HFE血色素沉着症患者而非非HFE血色素沉着症患者的十二指肠铁还原酶活性增加。Spearman等级相关性分析表明，Dcytb、hephaestin、FPN1和DMT1的mRNA表达彼此呈正相关，且与潜在疾病无关，这确保了吸收铁的有效跨上皮转运。
我们的数据表明，缺铁性贫血时十二指肠细胞色素b的活性通过增强蛋白质表达而被刺激，而在HFE血色素沉着症中，它在翻译后被上调。这表明缺铁性贫血和HFE血色素沉着症之间肠道铁吸收的动力学不同，也表明HFE和非HFE血色素沉着症中十二指肠铁蓄积在病理生理学上是不同的。
