In a recent article in Nanomedicine, Yingfang Fan and colleagues proposed a new approach to the treatment of iron overload (3). They used pH-sensitive gelatin nanoparticles for oral delivery of siRNA targeting divalent metal transport 1 (DMT1). They found that they could decrease DMT1 expression in the mouse gut, and consequently absorption of Fe59. This approach, the authors argued, presented advantages over the use of iron chelators, which lack specificity. This is an interesting new angle in the treatment of iron overload, although the authors have yet to test the efficacy of their method in hemochromatosis mice. What is the translational potential of this approach?. Well, the oral delivery through pH-sensitive nanoparticles appears to ensure specificity for gut DMT1. Indeed the authors reported that their nanoparticles did not affect DMT1 expression in other tissues.
One pertinent question is the effect of DMT1 blockade on iron levels, and consequently on the HIF-2α/FPN axis that regulates intestinal iron absorption. This is a space to watch………………
Of importance is the role of iron not only in mammals, but also in the oceans, particularly after the various fertilization experiments that showed that iron is the limiting factor for the growth of phytoplankton. Iron is known to come from the dust of the continents and from hydrothermal vents at the bottom of the ocean, and it is present in a particulate form and in a dissolved form. Iron in the ocean is in the oxidised Fe(III) form, that is highly insoluble, so that it easily sinks and it is not clear how the organism living in the ocean can take it up. A partial answer is from a recent paper in nature by McQuaid and collaborators, in which they shown that the diatom Phaeodactylum tricornutum expresses on its membrane a transferrin-like molecule with high affinity for iron, ISIP2A, the deletion of which reduced iron incorporation and cell proliferation. The defects were restored after complementation with human transferrin. This phytotransferrin is a trans-membrane protein like the melanotransferrin, that also may transfer iron. This phytotransferrin is able to bind the small amount of soluble Fe(III) present in the ocean and to deliver it to the cell after internalization by endocytosis. Transferrin was previously thought to have originated in multicellular metazoa, but these data show that transferrin-like iron acquisition occurs also in monocellular organisms, the phytotransferrin probably evolved from phosphonate-binding periplasmic proteins before 671 million years ago. An important implication is the observation that transferrin needs carbonate to bind iron, and the affinity strong pH dependent, since it diminishes with carbonate protonization. This is exploited for the mammalian recycling of transferrin, but it may be a problem with the acidification of the ocean due to the CO2 recent excess. In fact the papers shows that an addition of CO2 in the medium reduces diatom iron uptake and cell replication. For example, under constant iron constant iron a doubling of CO2 concentration reduced iron uptake rates by 44% in the P. tricornutum. This may be relevant in an environment in which productivity and CO2 consumption is limited by iron.
Folgueras AR, Freitas-Rodríguez S, Ramsay AJ, Garabaya C, Rodríguez F, Velasco G, López-Otín C. Nat Commun. 2018 Apr 10;9(1):1350 PDF
Commentary by Dr Gautam Rishi and Prof Nathan Subramaniam Liver Disease and Iron Disorders Research Group, Queensland University of Technology, Brisbane.
Iron dysfunction is associated with many clinical conditions including neurodegenerative disorders, cancers, the anemia associated with chronic disease, and many iron disorders. Several studies have also linked disturbed iron regulation with metabolic disorders including obesity; however in most cases it is linked to iron deficiency, with chronic inflammation identified as a possible cause. The iron regulatory hormone hepcidin is regulated by a number of proteins and various stimuli. Matriptase-2, encoded by TMPRSS6, is thought to be a repressor of hepcidin expression through its cleavage of the positive regulator, hemojuvelin (encoded by HJV). A deficiency of matriptase-2 in humans is associated with a form of anemia termed iron-refractory iron deficiency anemia (IRIDA).
This study by Folgueras et al, from the laboratory of Prof Carlos Lopez-Otin, demonstrates that mice with deficiency of matriptase-2 are protected from obesity induced by a high-fat diet. The authors demonstrate, and ascribe this protective effect to the increased breakdown of fat/lipids in matriptase-2 deficient mice resulting in decreased fat deposition. Surprisingly, the authors observed decreased levels of the “hunger hormone” leptin and a concomitant increase in food intake in matriptase-2 knockout mice which however showed decreased weight gain. Matriptase-2 knockout mice fed a high fat diet also had decreased liver steatosis and improved glucose tolerance. Decreasing hepcidin expression in matriptase-2 knockout mice through use of a neutralizing antibody against HJV reversed these effects. In summary these exciting studies demonstrate an important role for hepcidin and thus iron regulation in lipid homeostasis and function of adipocytes, opening new avenues in the fight against obesity.