Lack of haptoglobin affects iron transport across duodenum by modulating ferroportin expression.
OBJECTIVE
Haptoglobin is an acute phase protein responsible for the recovery of free hemoglobin from plasma. Haptoglobin-null mice were previously shown to have an altered heme-iron distribution, thus reproducing what occurs in humans in cases of congenital or acquired anhaptoglobinemia. Here, we report the analysis of iron homeostasis in haptoglobin-null mice.


METHODS
Iron absorption was measured in tied-off duodenal segments. Iron stores were evaluated on tissue homogenates and sections. The expression of molecules involved in iron homeostasis was analyzed at the protein and messenger RNA levels both in mice and in murine RAW264.7 macrophages stimulated in vitro with hemoglobin.


RESULTS
Analysis of intestinal iron transport reveals that haptoglobin-null mice export significantly more iron from the duodenal mucosa to plasma compared with control counterparts. Increased iron export from the duodenum correlates with increased duodenal expression of ferroportin, both at the protein and messenger RNA levels, whereas hepatic hepcidin expression remains unchanged. Up-regulation of the ferroportin transcript, but not of the protein, also occurs in haptoglobin-null spleen macrophages, which accumulate free hemoglobin-derived iron. Finally, we demonstrate that hemoglobin induces ferroportin expression in RAW264.7 cells.


CONCLUSIONS
Taking together these data, we suggest that haptoglobin, by controlling plasma levels of hemoglobin, participates in the regulation of ferroportin expression, thus contributing to the regulation of iron transfer from duodenal mucosa to plasma.
Marro
Samuele
S
Department of Genetics, Biology and Biochemistry, and Molecular Biotechnology Center, University of Torino, Torino, Italy.
Barisani
Donatella
D
Chiabrando
Deborah
D
Fagoonee
Sharmila
S
Muckenthaler
Martina U
MU
Stolte
Jens
J
Meneveri
Raffaella
R
Haile
David
D
Silengo
Lorenzo
L
Altruda
Fiorella
F
Tolosano
Emanuela
E
D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004386:Duodenum / Q000378:metabolism*; D006242:Haptoglobins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006706:Homeostasis; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D015854:Up-Regulation; D000098742:Ferroportin
D027682:Cation Transport Proteins; D006242:Haptoglobins; D006454:Hemoglobins; D012333:RNA, Messenger; D014168:Transferrin; D000098742:Ferroportin; D007501:Iron