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Liver non-transferrin bound iron uptake in vivo is iron regulated in hereditary haemochromatosis

Trinder, D., Delima, R.D., Chua, A.C.G., Ho, D., Graham, R.M. and Olynyk, J.K. (2011) Liver non-transferrin bound iron uptake in vivo is iron regulated in hereditary haemochromatosis. Journal of Gastroenterology and Hepatology, 26 (Supp. 4). p. 7.

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In hereditary haemochromatosis (HH), a common iron overload disorder, plasma non-transferrin-bound iron (NTBI) levels are increased. NTBI plays an important role in the pathogenesis of liver iron overload in HH however, the mechanism responsible for tissue NTBI uptake remains poorly defined. The aim of this study was to investigate NTBI transport in vivo in murine models of HH.

Methods NTBI transport was determined in Hfe knockout (Hfe−/−), Tfr2 Y245X mutant (Tfr2mut) and double mutant (Hfe−/−xTfr2mut) mouse models of HH, as well as wild-type and dietary iron loaded wild-type mice. Initially, serum transferrin was saturated with ferric citrate and then the mice were injected intravenously with NTBI in the form of 59-Fe citrate. Blood samples were collected at 2, 10, 30 min and tissues at 30 min and counted for radioactivity. Plasma NTBI concentration was measured biochemically and liver iron concentration was measured by ICP-atomic emission spectroscopy.

Results Plasma NTBI levels were increased in all HH and dietary iron-loaded mice compared to wild-type mice (p < 0.01), with the greatest increase (7-fold) observed in Hfe−/−xTfr2mut mice. 59Fe-NTBI was cleared from the plasma in HH and dietary iron loaded mice at a significantly greater rate than wild-type mice (p < 0.01). Most of the 59Fe-NTBI was taken up by the liver, followed by the kidneys, pancreas, heart and duodenum. In the liver, Hfe−/−xTfr2mut mice took up approximately 6-fold more 59Fe-NTBI than wild-type mice, while Hfe−/−, Tfr2mut and dietary iron-loaded mice took up to 3–4 fold more 59Fe-NTBI than wild-type mice (p < 0.01). Liver 59Fe-NTBI uptake was strongly correlated with liver iron concentration in all mice (r = 0.79; p < 0.0001). The amount of 59Fe-NTBI taken up by the kidney, pancreas, heart and duodenum in HH and dietary iron-loaded mice was also significantly increased compared with wild-type mice (p < 0.01).

Conclusions This study demonstrates for the first time in vivo NTBI transport in mouse models of HH. The liver was the main site of NTBI uptake and it was significantly increased in the mouse models of HH. Liver NTBI uptake was regulated by the liver iron concentration and is likely to contribute to the excessive liver iron deposition in HH.

Item Type: Journal Article
Publisher: Wiley-Blackwell
Notes: Abstract from Australian Gastroenterology Week 2011, Brisbane Convention & Exhibition Centre, 12 - 15 September 2011
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