Ablation of Na+/H+ exchanger‐3 prevents iron loading in the Hfe mouse model of hereditary hemochromatosis

Abstract

Iron deficiency is the most prevalent micronutrient deficiency worldwide. Meanwhile, several common hereditary disorders result in iron overload (hemochromatosis) and subsequently liver disease, cardiomyopathy, and endocrine disorders. Since there exists no regulated mechanism for the excretion of iron, systemic iron homeostasis is achieved by tightly regulating iron absorption. We have demonstrated that the H+‐coupled divalent metal‐ion transporter‐1 (DMT1) is essential for the uptake of nonheme iron at the apical membrane of intestinal enterocytes [Shawki A et al (2015) Am J Physiol Gastrointest Liver Physiol 309, G635–G647]. DMT1 is a validated therapeutic target in hereditary hemochromatosis. More recently, we identified a role for the intestinal brush‐border Na+/H+ exchanger‐3 (NHE3) in driving iron absorption by generating the H+ gradient to energize DMT1 [Shawki A et al (2016) Am J Physiol Gastrointest Liver Physiol 311, G423–G430]. Here we tested the hypothesis that pathological iron loading depends on the activity of NHE3. We examined the effects of ablating NHE3 on the iron‐overload phenotype of the Hfe mouse model of hereditary hemochromatosis. We crossed the NHE3 and Hfe knockout lines (on the FVB/N background) and examined (at age ≈ 120 d) hematological variables, and tissue and blood iron status in male and female offspring fed a standard diet (NIH‐07). The increased nonheme iron observed in the livers of Hfe‐null mice relative to wildtype mice was absent in the double null (Hfe−/− | NHE3−/−) (n = 89, 2‐way interaction P < 0.001), an effect that did not differ by sex (no 3‐way interaction, P = 0.54). Liver histology, using Perls' Prussian blue stain to detect iron deposits, supported this finding. NHE3 knockout also normalized serum iron levels in the Hfe null. Our data reveal that ablation of NHE3 prevents iron loading in the Hfe mouse model of hereditary hemochromatosis, and present the possibility of targeting intestinal NHE3 in the treatment of iron overload.Support or Funding InformationNIH grants R01 DK080047, R01 DK107309, P30 DK078392, and R25 HL115473, and the American Physiological SocietyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.