Abstract
Iron absorption requires an acidic environment that is generated by the activity of the proton pump gastric H(+)/K(+)ATPase (ATP4), expressed in gastric parietal cells. However, hepcidin, the iron regulatory peptide that inhibits iron absorption, unexpectedly upregulates ATP4 and increases gastric acidity. Thus, a concept of link between acidosis and alterations in iron metabolism, needs to be explored. We investigated this aspect in-vivo using experimental models of NH4Cl-induced acidosis and of an iron-rich diet. Under acidosis, gastric ATP4 was augmented. Serum hepcidin was induced and its mRNA level was increased in the liver but not in the stomach, a tissue where hepcidin is also expressed. mRNA and protein levels of intestinal DMT1(Divalent Metal Transporter 1) and ferroportin were downregulated. Serum iron level and transferrin saturation remained unchanged, but serum ferritin was significantly increased. Under iron-rich diet, the protein expression of ATP4A was increased and serum, hepatic and gastric hepcidin were all induced. Taken together, these results provide evidence of in-vivo relationship between iron metabolism and acidosis. For clinical importance, we speculate that metabolic acidosis may contribute in part to the pathologic elevation of serum hepcidin levels seen in patients with chronic kidney disease. The regulation of ATP4 by iron metabolism may also be of interest for patients with hemochromatosis.
Highlights
Iron from the diet goes through several processes before being absorbed across the epithelium of the proximal small intestine, and the regulation of iron absorption is essential for maintaining iron levels in the body within a physiologically defined range.To be absorbed, diet ferric iron (Fe(III)) is rapidly reduced to the ferrous form (Fe(II)) by the apical reductase Duodenal cytochrome B (Dcyt B) [1] and transported by the duodenum through the Divalent Metal Transporter 1 (DMT1) located at the apical membrane
Quantitative Reverse Transcriptase PCR (RT-PCR) and Western Blot experiments were performed, and the analyses revealed a significant increase in the transcript level of Atp4A (p = 0.019) (Figure 1A) and its protein expression (Figure 1B) in the stomachs of acidosis mice compared with control mice
Using a mouse experimental model of acidosis, the results demonstrate that gastric ATP4 expression was increased as described in previous studies [30,31], confirming that the current model mimic metabolic acidosis, as we have already shown in a rat [32]
Summary
Iron from the diet goes through several processes before being absorbed across the epithelium of the proximal small intestine, and the regulation of iron absorption is essential for maintaining iron levels in the body within a physiologically defined range.To be absorbed, diet ferric iron (Fe(III)) is rapidly reduced to the ferrous form (Fe(II)) by the apical reductase Duodenal cytochrome B (Dcyt B) [1] and transported by the duodenum through the Divalent Metal Transporter 1 (DMT1) located at the apical membrane. Fe(II) is exported into the blood through the iron exporter Ferroportin (FPN) located at the basolateral membrane of the enterocyte, where it is oxidized again into Fe(III) and bound to transferrin (Tf) before distribution to other tissues [2,3,4,5]. This availability of iron is largely dependent on the intraluminal gastric acid secretion. DMT1 operates as a symporter of divalent metal ions and H+, while the proton electrochemical potential gradient is the driving force for the metal transport [4]
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