A new study in the December Cell Metabolism reveals an unexpected connection between a tumor suppressor gene in the liver and the normally careful control over the amount of iron absorbed from the diet.
The surprising finding demonstrates a critical role for the liver in iron metabolism. The discovery also suggests a new avenue for the treatment of hereditary hemochromatosis, an iron-overload disease that is one of the most common genetic disorders among Caucasians, according to researchers.
Chu-Xia Deng, from the National Institute of Diabetes and Digestive and Kidney Diseases, and his colleagues report that mice lacking the SMAD4 gene in the liver only suffer from a toxic buildup of iron, particularly in their liver, kidneys, and pancreas--symptoms similar to those exhibited by humans with hemochromatosis. In other respects, the animals appeared remarkably normal, the researchers found.
"Unexpectedly, the liver-specific knockout of SMAD4 does not have a major impact on liver development; instead it results in a dramatic accumulation of iron in the liver of mutant mice," Deng said. "In addition, several other organs with intact SMAD4, including pancreas, kidney, eye, and brain, also exhibit accumulation of iron starting from 2 months of age.
"Our work not only creates a new animal model for the study of hemochromatosis but also clearly indicates that the liver is a physiological center for regulation of iron homeostasis," he added.
Iron is an essential nutrient found in many foods, particularly in red meat and iron-fortified bread and cereal. In the body, iron becomes part of hemoglobin, a molecule in the blood that transports oxygen from the lungs to all body tissues. Iron deficiency results in anemia, whereas iron overload leads to organ and tissue damage.
Symptoms of hemochromatosis, the most common iron-overload disease, can include bronzed skin, enlarged liver, diabetes, and abnormalities of the pancreas and joints. Frequent removal of blood in the same manner applied to blood donors can lower iron levels and alleviate the symptoms. Without treatment, the disease can lead to organ failure.
In the current study, the researchers set out to explore SMAD4's role in liver development and maintenance, by creating mice with normal levels of the gene in all part of the body except the liver. A member of a critical cell signaling pathway known as the transforming growth factor ß (TGF-ß) superfamily, SMAD 4 plays many central roles in development.
Earlier studies had also linked abnormalities in SMAD4 to multiple forms of cancer. For example, mutations in the tumor suppressor gene are frequently detected in pancreatic cancer, colon cancer, and a common form of lung cancer called adenocarcinoma, Deng said.
"Yet we didn't see cancer in the mice and saw only minor defects in the liver," Deng said. "Still, the mice were sick with apparent problems in their pancreas and other organs. Initially, we had no information to suggest that the gene might play a role in iron balance."