TY - JOUR
T1 - A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression
AU - Wang, Rui Hong
AU - Li, Cuiling
AU - Xu, Xiaoling
AU - Zheng, Yin
AU - Xiao, Cuiying
AU - Zerfas, Patricia
AU - Cooperman, Sharon
AU - Eckhaus, Michael
AU - Rouault, Tracey
AU - Mishra, Lopa
AU - Deng, Chu Xia
N1 - Funding Information:
We thank Y. Zhang for plasmids containing SMAD4 expression unit and S.P.S. Monga for Hepa1-6 cells. We are grateful for D. LeRoith, C.C. Philpott, and members of the Deng laboratory for useful discussion and critical reading of the manuscript. This research was supported by the Intramural Research Program of the Institute of Digestive and Kidney Diseases, National Institutes of Health.
PY - 2005/12
Y1 - 2005/12
N2 - Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-β, BMP, or IL-6. Our study uncovers a novel role of TGF-β/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis.
AB - Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-β, BMP, or IL-6. Our study uncovers a novel role of TGF-β/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis.
UR - https://www.scopus.com/pages/publications/33644876815
UR - https://www.scopus.com/pages/publications/33644876815#tab=citedBy
U2 - 10.1016/j.cmet.2005.10.010
DO - 10.1016/j.cmet.2005.10.010
M3 - Article
C2 - 16330325
AN - SCOPUS:33644876815
SN - 1550-4131
VL - 2
SP - 399
EP - 409
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -