Intestinal Dmt1 is Required for Iron Loading in Mice Modeling β-Thalassemia Intermedia

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R1912.

ABSTRACT

β-thalassemia intermedia (βTI) is characterized by chronic anemia, ineffective erythropoiesis, and excessive intestinal iron absorption leading to systemic iron overload. Divalent metal-ion transporter 1 (DMT1), the main intestinal iron transporter, may mediate excessive iron absorption in Th3/+ mice, which model βTI.

OBJECTIVE: To determine if intestinal DMT1 is required for iron-loading in beta-thalassemia, and if so, to utilize a ginger nanoparticle-derived lipid vector (GDLVs) siRNA delivery system to normalize iron absorption in Th3/+ mice.

HYPOTHESIS: DMT1 mediates excessive iron absorption in βTI mice and decreasing DMT1 expression by GDLVs-siRNA will prevent iron accumulation in these mice.

METHODS: Th3/+ mice were crossed with mice lacking intestinal DMT1 generating double KOs. Also, weanling mice were gavaged daily for 16 days with GDLVs carrying functional DMT1 siRNA, and iron absorption and iron loading were assessed.

RESULTS: Liver, spleen, kidney, heart, and duodenum non-heme iron levels were decreased in Th3/+ mice lacking intestinal DMT1. Serum non-heme iron content, serum ferritin levels, and transferrin saturation also decreased in Th3/+ mice lacking intestinal DMT1. Splenomegaly was alleviated in the double KO mice. Oral gavage of GDLVs carrying DMT1 siRNA blunted intestinal DMT1 expression and mitigated hepatic and splenic iron loading. Serum non-heme iron levels, serum ferritin, and transferrin saturation also decreased in Th3/+ mice receiving GDLVs with DMT1 siRNA.

CONCLUSION: Intestinal DMT1 is required for iron-loading in Th3/+ mice, and in vivo DMT1 knock down is an effective approach to blunt iron loading in mice modeling βTI.

PMID:35556450 | DOI:10.1096/fasebj.2022.36.S1.R1912