Abstract
Abnormal calcium absorption and iron overload from iron hyperabsorption can contribute to osteoporosis as found in several diseases, including hemochromatosis and thalassemia. Previous studies in thalassemic mice showed the positive effects of the iron uptake suppressor, hepcidin, on calcium transport. However, whether this effect could be replicated in other conditions is not known. Therefore, this study aimed to investigate the effects of hepcidin on iron and calcium uptake ability under physiological, iron uptake stimulation and calcium uptake suppression. To investigate the potential mechanism, effects of hepcidin on the expression of iron and calcium transporter and transport-associated protein in Caco-2 cells were also determined. Our results showed that intestinal cell iron uptake was significantly increased by ascorbic acid together with ferric ammonium citrate (FAC), but this phenomenon was suppressed by hepcidin. Interestingly, hepcidin significantly increased calcium uptake under physiological condition but not under iron uptake stimulation. While hepcidin significantly suppressed the expression of iron transporter, it had no effect on calcium transporter expression. This indicated that hepcidin-induced intestinal cell calcium uptake did not occur through the stimulation of calcium transporter expression. On the other hand, 1,25(OH)2D3 effectively induced intestinal cell calcium uptake, but it did not affect intestinal cell iron uptake or iron transporter expression. The 1,25(OH)2D3-induced intestinal cell calcium uptake was abolished by 12 mM CaCl2; however, hepcidin could not rescue intestinal cell calcium uptake suppression by CaCl2. Taken together, our results showed that hepcidin could effectively and concurrently induce intestinal cell calcium uptake while reducing intestinal cell iron uptake under physiological and iron uptake stimulation conditions, suggesting its therapeutic potential for inactive calcium absorption, particularly in thalassemic patients or patients who did not adequately respond to 1,25(OH)2D3.
Highlights
Low bone mass, osteopenia and osteoporosis were shown in several diseases with iron overload, such as hereditary hemochromatosis and β-thalassemia [1,2,3,4,5,6,7]
Whether hepcidin-induced intestinal calcium absorption and its inhibitory effect on intestinal iron absorption could be replicated in other conditions beside thalassemia is not known
Our results demonstrated that while hepcidin significantly suppressed intestinal cell iron uptake, it could not markedly elevate intestinal cell calcium uptake in Caco-2 cells under iron uptake stimulation
Summary
Osteopenia and osteoporosis were shown in several diseases with iron overload, such as hereditary hemochromatosis and β-thalassemia [1,2,3,4,5,6,7]. While iron overload and intestinal iron hyperabsorption were reported, the ineffective calcium absorption was found in these patients and animal models [1, 8,9,10,11]. Because intestinal iron hyperabsorption was evident in animal models and patients with iron overload-associated osteoporosis, the alteration in intestinal iron transport regulation in these cases was elucidated. We found that ineffective calcium absorption could significantly be improved by the iron transport suppressor, hepcidin, in thalassemic mice [15]. This study has provided information regarding the effectiveness and the conditions that hepcidin could be used to improve intestinal calcium absorption This will be the crucial step for the application of hepcidin to alleviate both iron hyperabsorption and ineffective calcium absorption simultaneously
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