Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice

Zhuzhen Zhang, Fan Zhang, Xin Guo, Peng An, Yunlong Tao, Fudi Wang

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


The liver is a major site of iron storage where sequestered iron can be actively mobilized for utilization when needed elsewhere in the body. Currently, hepatocyte iron efflux mechanisms and their relationships to macrophage iron recycling during the control of whole-body iron homeostasis are unclear. We hypothesized that the iron exporter, ferroportin1 (Fpn1), is critical for both iron mobilization from hepatocytes and iron recycling from macrophages. To test this, we generated hepatocyte-specific Fpn1 deletion mice (Fpn1Alb/Alb) and mice that lacked Fpn1 in both hepatocytes and macrophages (Fpn1Alb/Alb;LysM/LysM). When fed a standard diet, Fpn1Alb/Alb mice showed mild hepatocyte iron retention. However, red blood cell (RBC) counts and hemoglobin (Hb) levels were normal, indicating intact erythropoiesis. When fed an iron-deficient diet, Fpn1Alb/Alb mice showed impaired liver iron mobilization and anemia, with much lower RBC and Hb levels than Fpn1flox/flox mice on the same diet. Using a strategy where mice were preloaded with differing amounts of dietary iron before iron deprivation, we determined that erythropoiesis in Fpn1Alb/Alb and Fpn1flox/flox mice depended on the balance between storage iron and iron demands. On a standard diet, Fpn1Alb/Alb;LysM/LysM mice displayed substantial iron retention in hepatocytes and macrophages, yet maintained intact erythropoiesis, implying a compensatory role for intestinal iron absorption. In contrast, when Fpn1Alb/Alb;LysM/LysM mice were fed an iron-deficient diet, they developed severe iron-deficiency anemia, regardless of their iron storage status. Thus, Fpn1 is critical for both hepatocyte iron mobilization and macrophage iron recycling during conditions of dietary iron deficiency. Conclusion: Our data reveal new insights into the relationships between Fpn1-mediated iron mobilization, iron storage, and intestinal iron absorption and how these processes interact to maintain systemic iron homeostasis.

Original languageEnglish (US)
Pages (from-to)961-971
Number of pages11
Issue number3
StatePublished - Sep 2012
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology


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