4-fold (Fig 5A), whereas duodenal BMP6 mRNA expression was large

4-fold (Fig. 5A), whereas duodenal BMP6 mRNA expression was largely unaffected (Fig. 5B). The expression of ferroportin was markedly up-regulated in the duodenum of mice lacking hepatic Hjv (Fig. 5C). We conclude that hepatic Hjv is essential for preventing iron overload by way of appropriate signaling to hepcidin. Hfe2f/f:MCK-Cre mice bearing muscle-specific disruption of Hjv presented with

physiological serum iron indices (Table 2) and did not develop iron overload in the liver, pancreas, or, notably, in the heart (Fig. 4A; Supporting Fig. S1). Splenic macrophages contained stainable nonheme iron (Fig. S1), by analogy to Hfe2f/f controls. The expression of hepcidin mRNA (Fig. 4B), hepatic BMP6 mRNA (Fig. 5A), and duodenal BMP6 mRNA (Fig. 5B) did not significantly differ between Hfe2f/f:MCK-Cre and Hfe2f/f mice, whereas expression of duodenal ferroportin was Rapamycin undetectable

(Fig. 5C). Thus, the absence of muscle Hjv did not affect iron metabolism in the whole body and, apparently, also in the heart, a tissue that normally expresses Hjv. We compared Selleck Peptide 17 the hepatic iron content and hepcidin mRNA expression levels among age- and sex-matched Hfe2f/f, Hfe2f/f:Alb-Cre, Hfe2f/f:MCK-Cre, and ubiquitous Hjv-/-7 mice; all lines shared a mixed 129S6/C57 genetic background, albeit with variable genomic ratios. The degree of hepatic iron overload (Fig. 4A), the deregulation of hepcidin expression (Fig. 4B), and the increase of hepatic BMP6 mRNA (Fig. 5B) were quantitatively similar among ubiquitous Hjv−/− and liver-specific Hjv−/− (Hfe2f/f:Alb-Cre) animals. Likewise, control floxed (Hfe2f/f) and muscle-specific Hjv−/− (Hfe2f/f:MCK-Cre) mice were phenotypically indistinguishable. Taken together, these results indicate that the absence of hepatic Hjv suffices to cause full-scale iron overload, whereas the lack of muscle Hjv does

not affect iron balance. Genetic studies in humans5 and mice6, 7 uncovered an important role of Hjv in the control of systemic iron homeostasis. Corroborating evidence was selleck chemical provided from biochemical data showing that Hjv activates the iron-dependent pathway for signaling to hepcidin by acting as a BMP coreceptor,8 whereas a circulating sHjv isoform is widely considered to antagonize this response.19, 20, 22, 31 We report here that the targeted disruption of Hjv in liver hepatocytes recapitulates the hemochromatotic phenotype of mice lacking Hjv ubiquitously.6, 7 Thus, the liver-specific ablation of Hjv leads to high transferrin saturation, hyperferremia, hyperferritinemia, hepatic iron overload, macrophage iron deficiency, and inappropriately low hepcidin expression, which are hallmarks of hereditary hemochromatosis. In addition, it is associated with increased hepatic BMP6 mRNA expression, as in ubiquitous Hjv−/− mice.

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