Interrelationships between circulating gastrin and iron status in mice and humans

Abstract

The observations that the peptide hormone gastrin interacts with transferrin in vitro and that circulating gastrin concentrations are increased in the iron-loading disorder hemochromatosis suggest a possible link between gastrin and iron homeostasis. This study tested the hypothesis that gastrin and iron status are interrelated by measurement of iron homeostasis in mice and humans with abnormal circulating gastrin concentrations. Intestinal iron absorption was determined by59Fe uptake following oral gavage, and concentrations of duodenal divalent metal transporter-1 (DMT-1) and hepatic hepcidin mRNAs were determined by quantitative real-time PCR in agastrinemic (GasKO), hypergastrinemic cholecystokinin 2 receptor-deficient (CCK2RKO), or wild-type mice. Iron status was measured by standard methods in the same mice and in hypergastrinemic humans with multiple endocrine neoplasia type 1 (MEN-1). Iron absorption was increased sixfold and DMT-1 mRNA concentration fourfold, and transferrin saturation was reduced 0.8-fold and hepcidin mRNA expression 0.5-fold in juvenile GasKO mice compared with age-matched wild-type mice. In mature mice, few differences were observed between the strains. Juvenile CCK2RKO mice were hypergastrinemic and had a 5.4-fold higher DMT-1 mRNA concentration than wild-type mice without any increase in iron absorption. In contrast to juvenile GasKO mice, juvenile CCK2RKO mice had a 1.5-fold greater transferrin saturation, which was reflected in a twofold increase in liver iron deposition at maturity compared with wild-type mice. The correlation between transferrin saturation and circulating gastrin concentration observed in mutant mice was also observed in human patients with MEN, in whom hypergastrinemia correlated positively ( P = 0.004) with an increased transferrin saturation. Our data indicate that, in juvenile animals when iron demand is high, circulating gastrin concentrations may alter iron status by a CCK2R-independent mechanism.

Gastric secretion

“…As gastrin and transferrin are known to bind two ferric ions, one may postulate that gastrin may act as a chaperone for the uptake of ferric iron by transferrin. In support of this notion, a positive correlation has been reported between circulating gastrin concentration and transferrin saturation [19] and apo-transferrin (iron-free transferrin) binds two gastrin molecules.…”

Gastrins, iron homeostasis and colorectal cancer

“…The concentration of hepcidin mRNA in the gastric mucosa of Gas −/− mice was only 40% of the value in wild-type mice, but returned to 130% of the wild-type value after subcutaneous infusion of Gamide for 1 week [83]. In juvenile Gas −/− mice, intestinal iron absorption measured by 59 Fe uptake after oral gavage was increased sixfold, and concentrations of Dmt-1 mRNA were increased fourfold, compared with age-matched wild-type mice [6]. The increased absorption probably reflects systemic iron deficiency in these animals and the reduction in hepatic hepcidin expression supports this proposal [6].…”

“…In juvenile Gas −/− mice, intestinal iron absorption measured by 59 Fe uptake after oral gavage was increased sixfold, and concentrations of Dmt-1 mRNA were increased fourfold, compared with age-matched wild-type mice [6]. The increased absorption probably reflects systemic iron deficiency in these animals and the reduction in hepatic hepcidin expression supports this proposal [6]. Although there was no significant change in iron absorption in hypergastrinemic Cck2r −/− mice, Dmt-1 mRNA was 5.4-fold higher than in age-matched wild-type mice.…”

“…Importantly, transferrin saturation was reduced by 20% in Gas −/− mice, and increased by 50% in Cck2r −/− mice, compared to age-matched wild-type mice. Similarly, in humans hypergastrinemic because of multiple endocrine neoplasia type I, transferrin saturation correlated positively with circulating Gamide concentrations [6]. …”

“…The recognition that iron-deficiency anemia was a long-term consequence of partial gastrectomy indicated the importance of gastric acid in the absorption of dietary iron [2, 3]. However over the past decade evidence has been accumulating that gastrin and its precursors may be directly involved in iron homeostasis [4–6]. Since gastrin precursors also act as growth factors for the colorectal mucosa [7, 8], this review will explore the connections between gastrins and iron homeostasis, and the implications of those connections for the development of colorectal cancer.…”