Age and gender dependent differences in BMP6 mediated hepcidin expression and iron homeostasis

Intestinal iron absorption is critical for normal iron balance, and it is regulated by hepcidin which is synthesized predominantly in the liver. Dysregulation of hepcidin production induces many iron related disorders, and increased (hepatic) iron levels have been shown to promote the progression of chronic liver diseases. Recently, we have shown that bone morphogenetic protein 6 (BMP6) is the master endogenous regulator of hepcidin and that it is produced predominantly in the small intestine but not in the liver (Gastroenterology 2010; 138 (1): 372–82).

We expanded these studies to a comparison between male and female mice of different age to investigate whether there are differences that may also account for age and gender dependent variation in the progression of chronic liver disease. Interestingly, BMP6 deficient mice (BMP6-/-) on a 129Sv/Ev background fed with normal diet developed severe hepatic iron accumulation and reduced hepcidin expression with increasing age. It is important to note that the phenotype of hepatic iron accumulation and reduced hepcidin expression could be triggered in younger mice by feeding iron-supplemented diets or parenteral application of iron-dextran. Both treatments induced a marked upregulation of BMP6 expression in the small intestine and higher BMP6 serum levels. These results suggest that intestinal BMP6 is transported via the bloodstream to the liver for hepcidin regulation. One further interesting new finding was that male mice showed significantly lower hepcidin levels and higher hepatic iron-overload after feeding an iron-supplemented diet than female mice of the same age.

In conclusion, we observed age and gender dependent differences with regards to BMP6 and hepcidin expression under basal conditions as well as in response to iron overload. We speculate that these findings accounts at least in part for age and gender dependent differences in the progression of chronic liver diseases.

BMP6 - hepcidin - iron metabolism - mouse model