New discovery on iron metabolism improves anemia treatment

- FR- EN

Anemia is a major public health problem worldwide, affecting around a third of the population. There are many causes of anemia, but the most common are a defect in the production of red blood cells, a lack of iron in the blood or genetic diseases such as thalassemia. A better understanding of iron metabolism is essential to improve management of the many patients affected. In a new study, Inserm researchers at the Institut de recherche en santé digestive (Inserm/INRAE/université Toulouse III - Paul-Sabatier/École nationale vétérinaire de Toulouse), have identified the major role played by a protein called FGL1 in iron metabolism. Their discovery opens the way to new clinical perspectives in the treatment of anemia. These results are published in the journal Blood .

Anemia is a condition in which the number of red blood cells - or the hemoglobin content of red blood cells - is below normal. It is a major public health problem. Indeed, it is a major factor in morbidity and mortality for a third of the world’s population.

Anemia can be caused by a deficiency of iron in the blood as a result of dietary deficiencies, infections, chronic illnesses, heavy menstruation, problems during pregnancy, or by genetic diseases affecting red blood cell production (thalassemias).

Iron is an essential element in many biological processes, such as the transport and storage of oxygen in the body, as an essential constituent of hemoglobin in red blood cells. In other words, when too little iron is present in the body, there isn’t enough hemoglobin and red blood cells to transport oxygen to organs and tissues, leading to organ failure.

However, excess iron is also toxic to the body. Iron intake must therefore be carefully regulated to avoid deficiency or excess, which can lead to severe clinical complications.

Understanding iron metabolism

Knowledge of anemia and iron metabolism has been growing steadily for several years. It is now well known that iron levels in the body are regulated by a hormone called hepcidin.

We also now know that when the body’s need for iron is increased, as in the case of anemia, a hormone called erythroferrone (ERFE) suppresses hepcidin expression in the liver. This process supplies the bone marrow with iron to synthesize new red blood cells and increase hemoglobin levels.

The identification of ERFE in 2014 by Inserm researcher Léon Kautz and colleagues was a milestone in this field of research. Nevertheless, these data obtained ten years ago already suggested that ERFE was not the only hormone controlling this process. The scientists’ hypothesis was that a second, hitherto unknown protein performed a similar function.

A new factor identified

They have now confirmed this by conducting new experiments in mouse models of anemia, in two specific cases: during increased red blood cell synthesis to correct induced anemia in mice, and in mice with thalassemia.

The scientists first studied the molecular mechanisms activated in the animals’ livers to identify the genes whose expression was increased during anemia. They found that expression of the gene encoding the FGL1 protein was increased in the liver when oxygen concentration fell.

The researchers then produced different forms of the FGL1 protein to test its mode of action in vivo in mice and in vitro in human liver cells. They were able to show that its mode of action is similar to that of the hormone ERFE, since FGL1 also represses hepcidin expression.

"In addition to the fundamental aspects of this work in understanding anemia, we believe that identifying the role of FGL1 will lead to the development of new therapeutic strategies for the treatment of anemias of diverse origins, for which current treatments are ineffective", stresses Léon Kautz, Inserm research scientist.

For the time being, the team will first carry out further work to verify that FGL1 levels are indeed increased in the blood of patients with different types of anemia. But the scientists intend to go even further. Inserm Transfert has already filed two patents for this study.

On the one hand, the first patent aims to better treat anemia resulting from chronic diseases such as cancer. The aim is to identify molecules analogous to or activating the synthesis of FGL1, which would reduce the expression of hepcidin in these patients and enable them to increase their hemoglobin levels.

On the other hand, thalassemias are characterized by very low levels of hepcidin, leading to organ-damaging iron overload and high mortality. The team hypothesized that FGL1 might also be involved in this process. The second patent therefore aims to provide proof of concept that inhibiting FGL1 could improve iron overload in patients suffering from thalassemia.