Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse

Divalent metal-ion transporter-1 (DMT1), the principal mechanism by which nonheme iron is taken up at the intestinal brush border, is energized by the H+-electrochemical potential gradient. The provenance of the H+ gradient in vivo is unknown, so we have explored a role for brush-border Na+/H+ exchanger (NHE) isoforms by examining iron homeostasis and intestinal iron handling in mice lacking NHE2 or NHE3. We observed modestly depleted liver iron stores in NHE2-null (NHE2–/–) mice stressed on a low-iron diet but no change in hematological or blood iron variables or the expression of genes associated with iron metabolism compared with wild-type mice. Ablation of NHE3 strongly depleted liver iron stores, regardless of diet. We observed decreases in blood iron variables but no overt anemia in NHE3-null (NHE3–/–) mice on a low-iron diet. Intestinal expression of DMT1, the apical surface ferrireductase cytochrome b reductase-1, and the basolateral iron exporter ferroportin was upregulated in NHE3–/– mice, and expression of liver Hamp1 (hepcidin) was suppressed compared with wild-type mice. Absorption of 59Fe from an oral dose was substantially impaired in NHE3–/– compared with wild-type mice. Our data point to an important role for NHE3 in generating the H+ gradient that drives DMT1-mediated iron uptake at the intestinal brush border.
Source: AJP: Gastrointestinal and Liver Physiology - Category: Gastroenterology Authors: Tags: NUTRIENT SENSING, NUTRITION, AND METABOLISM Source Type: research