Abstract
The peptide hormone hepcidin is a key controller of systemic iron homeostasis, and its expression in the liver is mainly regulated by bone morphogenetic proteins (BMPs), which are heparin binding proteins. In fact, heparins are strong suppressors of hepcidin expression in hepatic cell lines that act by inhibiting the phosphorylation of SMAD1/5/8 proteins elicited by the BMPs. The inhibitory effect of heparins has been demonstrated in cells and in mice, where subcutaneous injections of non-anticoagulant heparins inhibited liver hepcidin expression and increased iron bioavailability. The chemical characteristics for high anti-hepcidin activity in vitro and in vivo include the 2O-and 6O-sulfation and a molecular weight above 7 kDa. The most potent heparins have been found to be the super-sulfated ones, active in hepcidin suppression with a molecular weight as low as 4 kDa. Moreover, the alteration of endogenous heparan sulfates has been found to cause a reduction in hepcidin expression in vitro and in vivo, indicating that heparins act by interfering with the interaction between BMPs and components of the complex involved in the activation of the BMP/SMAD1/5/8 pathway. This review summarizes recent findings on the anti-hepcidin activity of heparins and their possible use for the treatment of anemia caused by hepcidin excess, including the anemia of chronic diseases.
Highlights
The biological function of heparins has not been fully established yet, but it is well known that they can bind a large number of plasma proteins with important biological roles that include growth factors, morphogens, and cytokines
In vitro studies on hepatic cells initially showed that BMP2 is a strong inducer of hepcidin, but later it was found that BMP6 is the physiological bone morphogenetic proteins (BMPs) dedicated to hepcidin expression based on the evidence that the major phenotype of mice deficient in BMP6 was a massive liver iron overload and that BMP6 is regulated in an iron-dependent manner [21]
The exogenous heparin is normally used to interfere with the physiological interactions between the ligands and endogenous heparan sulfates, it was of interest to verify if and how the heparan sulfates participate in the mechanism of hepcidin expression
Summary
The biological function of heparins has not been fully established yet, but it is well known that they can bind a large number of plasma proteins with important biological roles that include growth factors, morphogens, and cytokines. This occurs because heparin shares the same binding capacity as the heparan sulfates (HSs) bound to the surfaces of all mammalian cells. Molecules 2017, 22, 598 summarizes the recent development on mammalian iron homeostasis, its regulation and pathological deregulations, and the possible use of heparins for treatment of anemias caused by hepcidin excess, as it occurs in inflammatory conditions
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