Abstract
Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.
Highlights
Iron is an essential trace mineral with numerous notable biological functions
We previously demonstrated that in vivo knock down of intestinal divalent metal-ion transporter 1 (Dmt1) prevented iron loading in a weanling mouse model of early onset HH (i.e., Hamp KO mice)
We first sought to determine whether oral administration of FA-GDLVs caused intestinal inflammation or other untoward effects on experimental mice
Summary
Iron is an essential trace mineral with numerous notable biological functions. Iron homeostasis is unique among the dietary minerals as iron-excretory systems do not exist in humans or other mammals. Sophisticated homeostatic regulators of iron absorption have developed through evolutionary time, which collectively influence iron absorption in relation to body iron stores, erythroid demand, tissue oxygenation, and during infection and inflammation [1]. Hepcidin is a principal regulator of iron absorption. This liverderived, peptide hormone controls serum iron levels by regulating iron efflux from cells that absorb (duodenal enterocytes) and store (reticuloendothelial macrophages) iron [2]. The Hamp gene (encoding hepcidin) is transactivated in hepatocytes when iron stores are replete and during inflammation; increased hepcidin suppresses intestinal iron absorption and lowers serum iron. Hypoxia and when erythroid demand is elevated, Hamp transcription is downregulated, increasing intestinal iron transport and raising serum iron
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