Suppression of SLC11A2 Expression Is Essential to Maintain Duodenal Integrity During Dietary Iron Overload

Abstract

Iron is essential for the survival of mammals, but iron overload causes fibrosis and carcinogenesis. Reduced iron absorption and regulated release into circulation in duodenal mucosa constitute two major mechanisms of protection against dietary iron overload; however, their relative contribution remains elusive. To study the significance of the former process, we generated SLC11A2 transgenic mice (TGs) under the control of the chicken ␤-actin promoter. TGs were viable and fertile, and displayed no overt abnormalities up to 20 months. No significant difference in iron concentration was observed in major solid organs between TGs and their wild-type littermates, suggesting that increased number of iron transporters does not lead to increased iron absorption. To test the sensitivity to iron overload, TGs and wild-type mice were fed with an iron-rich diet containing 2% ferric citrate. Iron supplementation caused suppression of endogenous duodenal SLC11A2 expression, downregulation of duodenal ferroportin, and overexpression of hepatic hepcidin, precluding excessive iron uptake both in the TGs and wild-type mice. However, iron-treated TGs revealed increased mortality, resulting from oxidative mucosal damage leading to hemorrhagic erosion throughout the whole intestinal area. These findings suggest that reduced iron release from duodenal cells into circulation plays a role in mitigating excessive iron uptake from the diet and that finely regulated duodenal absorption is essential to protect intestinal mucosa from iron-induced oxidative damage.

Duodenal Absorption and Tissue Utilization of Dietary Heme and Nonheme Iron Differ in Rats

“…These changes were accompanied by a marked downregulation in duodenal Dmt1 mRNA, whereas duodenal Fpn mRNA had only a slight, but nonsignificant, decrease in response to iron injection and increased hepcidin production. Similar findings of an inverse association between hepatic hepcidin expression and duodenal iron transporter mRNA were observed in both iron-loaded mice (26) and rats (4,27). These changes are thought to occur in response to increases in intracellular iron, which could reduce transcript stability via the iron regulatory element/ iron regulatory protein system (28) or inhibit transcription by interfering with hypoxia inducible factor 2 (HIF-2) signaling (29).…”

Nonalcoholic Fatty Liver Disease Is Associated with Helicobacter pylori Infection in North Urban Chinese: A Retrospective Study

“…A variety of inflammatory cytokines are involved in H. pylori infection, with the closest relationships detected among CRP, TNF-α, IL-6, and interleukin-(IL-) 1β [23,24]. In addition, the formation of hepcidin in subjects with NAFLD increases the iron load and leads to iron-induced intestinal mucosal oxidative damage [25,26], which in turn increases acid load [27]. It has been suggested that increased acid load can precipitate bile acids and reduce bile inhibition by H. pylori, thereby increasing the risk of H. pylori infection [27].…”

Iron overload signature in chrysotile‐induced malignant mesothelioma

“…Anti‐C‐ERC/mesothelin monoclonal antibody was from IBL (Takasaki, Gunma, Japan). Anti‐8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) mouse monoclonal antibody N45.1 and anti‐rat DMT1 rabbit polyclonal antibody were used.…”