The Liver Is Important in the Storage and Homeostasis of Iron

The liver is the major site for the synthesis of several proteins involved in iron transport and metabolism. The protein transferrin plays a critical role in the transport and homeostasis of iron in the blood. The circulating plasma transferrin level is inversely proportional to the iron load of the body—the higher the concentration of ferritin in the hepatocyte, the lower the rate of transferrin synthesis. During iron deficiency, liver synthesis of transferrin is significantly stimulated, enhancing the intestinal absorption of iron. Haptoglobin, a large glycoprotein with a molecular weight of 100,000, binds free hemoglobin in the blood. The hemoglobin-haptoglobin complex is rapidly removed by the liver, conserving iron in the body. Hemopexin is another protein synthesized by the liver that is involved in the transport of free heme in the blood. It forms a complex with free heme, and the complex is removed rapidly by the liver.

The spleen is the organ that removes red blood cells that are slightly altered. Kupffer cells of the liver also have the capacity to remove damaged red blood cells, especially those that are moderately damaged (Fig. 28.8). The red cells taken up by Kupffer cells are rapidly digested by secondary lysosomes to release heme. Microsomal heme oxy-

Kupffer Cells

The possible pathways following phagocytosis of damaged red blood cells by Kupf-fer cells. (Modified from Young SP, Aisen P. The liver and iron. In: Arias I, Jakoby WB, Popper H, et al., eds. The Liver: Biology and Pathobiology. New York: Raven, 1988.)

genase releases iron from the heme, which then enters the free iron pool and is stored as ferritin or released into the bloodstream (bound to apotransferrin). Some of the ferritin iron may be converted to hemosiderin granules. It is unclear whether the iron from the hemosiderin granules is exchangeable with the free iron pool.

It was long believed that Kupffer cells were the only cells involved in iron storage, but recent studies suggest that hepatocytes are the major sites of long-term iron storage. Transferrin binds to receptors on the surface of hepa-tocytes, and the entire transferrin-receptor complex is internalized and processed (Fig. 28.9). The apotransferrin (not containing iron) is recycled back to the plasma, and the released iron enters a labile iron pool. The iron from transferrin is probably the major source of iron for the he-patocytes, but they also derive iron from haptoglobin-he-moglobin and hemopexin-heme complexes. When hemoglobin is released inside the hepatocytes, it is degraded in the secondary lysosomes, and heme is released. Heme is processed in the smooth ER and free iron released enters the labile iron pool. A significant portion of the free iron in the cytosol probably combines rapidly with apoferritin to form ferritin. Like Kupffer cells, hepatocytes may transfer some of the iron in ferritin to hemosiderin.

Iron is absolutely essential for survival, but iron overload can be extremely toxic, especially to the liver where it can cause hemochromatosis, a condition characterized by excessive amounts of hemosiderin in the hepatocytes. The hepatocytes in patients with hemochromatosis are defective and fail to perform many normal functions.

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