A healthy adult human produces over 200 billion red blood cells every single day. Each of these cells contains a protein known as haemoglobin, which is essential for transporting oxygen around our bodies and keeping us alive. Producing these blood cells, and the haemoglobin contained within them, requires iron, and lots of it. This is just one of the indispensable roles that iron plays within our bodies. It is an essential element for almost all living organisms, and without it, humans would not survive.
Unfortunately, you can always have too much of a good thing. Humans are unable to expel excess iron from our bodies, and if it builds up, it can become toxic and make us ill. Balancing the iron levels in our bodies, a process known as iron homeostasis, is a delicate act, but one that is key to our survival.
Dr Kostas Pantopoulos, a biomedical researcher at McGill University, and his former PhD student Dr Edouard Charlebois, currently post-doctoral fellow at the XSeed labs, are studying the complexities of iron regulation and homeostasis. Using genetically modified mice, they are exploring the role that the liver plays in keeping our iron levels balanced.
How does iron move around the body?
Our bodies cannot make iron, so all of the iron that we need must come from our diet. This iron is absorbed in the small intestine and passes into the bloodstream where it binds to transferrin, a protein that transports it around the body to the cells that need it.
When the transferrin reaches a cell, it binds to a receptor known as transferrin receptor 1 (Tfr1). “Tfr1 provides a docking site for transferrin and is essential for iron delivery to cells; this is why it is often called the ‘cellular iron gate’,” explains Kostas.
How does the body regulate iron?
The liver plays a central role in iron regulation. Not only is it the main site of excess iron storage in the body, but it also produces the hormone hepcidin which regulates how much iron we absorb from our diets.
Hepcidin is produced by cells in the liver called hepatocytes. As iron levels in our body increase, more of it begins to be stored in the liver. Hepatocytes sense when iron levels in the liver begin to rise and produce hepcidin to prevent us from absorbing any more iron. When iron levels are low, hepatocytes stop producing hepcidin so that we can start absorbing iron again.
Kostas and Edouard experimented with genetically modified mice to investigate the role that Tfr1 plays in this process of iron regulation in the liver. “We generated mice with specific disruption of Tfr1 in hepatocytes,” explains Kostas. “Surprisingly, we observed that the mice were developing normally and did not exhibit any signs of disease.” These results show that hepatocytes are able to acquire iron without the key transferrin receptor, Tfr1.
“Nevertheless, the mice had significantly less iron stored in their livers and were unable to adjust their production of hepcidin to balance their iron levels,” adds Kostas. “The most important conclusion of this study was that Tfr1 is not essential for supplying iron to hepatocytes but rather has a ‘systemic’ function in the control of hepcidin expression and overall body iron regulation.”
In order to carry out this systemic regulation, hepatocytes need to be able to sense the amount of iron in the body. The process by which hepatocytes do this is not well understood, and is another focus of Kostas and Edouard’s research.
How do hepatocytes sense iron levels in the liver?
“Earlier work suggests that circulating iron in the bloodstream and liver iron stores stimulate hepcidin expression by different mechanisms,” says Kostas. As we absorb iron into our bloodstream, transferrin molecules fill up and become saturated. This increase in transferrin saturation is sensed by another type of receptor, transferrin receptor 2 (Tfr2), which activates hepcidin production.
“The mechanism by which increased liver iron stores induce hepcidin is more complex and is not completely understood,” says Kostas. “We know that endothelial cells in the liver secrete proteins called bone morphogenic protein 6 (BMP6) and bone morphogenic protein 2 (BMP2) which bind to receptors on hepatocytes and activate the production of hepcidin.”
