Smad7 deficiency decreases iron and haemoglobin through hepcidin up‐regulation by multilayer compensatory mechanisms |
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| Authors: | Peng An Hao Wang Qian Wu Jiaming Wang Zhidan Xia Xuyan He Xinhui Wang Yan Chen Junxia Min Fudi Wang |
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| Affiliation: | 1. Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China;2. School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China;3. Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou, China;4. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China |
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| Abstract: | To maintain iron homoeostasis, the iron regulatory hormone hepcidin is tightly controlled by BMP‐Smad signalling pathway, but the physiological role of Smad7 in hepcidin regulation remains elusive. We generated and characterized hepatocyte‐specific Smad7 knockout mice (Smad7Alb/Alb), which showed decreased serum iron, tissue iron, haemoglobin concentration, up‐regulated hepcidin and increased phosphor‐Smad1/5/8 levels in both isolated primary hepatocytes and liver tissues. Increased levels of hepcidin lead to reduced expression of intestinal ferroportin and mild iron deficiency anaemia. Interestingly, we found no difference in hepcidin expression or phosphor‐Smad1/5/8 levels between iron‐challenged Smad7Alb/Alb and Smad7flox/flox, suggesting other factors assume the role of iron‐induced hepcidin regulation in Smad7 deletion. We performed RNA‐seq to identify differentially expressed genes in the liver. Significantly up‐regulated genes were then mapped to pathways, revealing TGF‐β signalling as one of the most relevant pathways, including the up‐regulated genes Smad6, Bambi and Fst (Follistatin). We found that Smad6 and Bambi—but not Follistatin—are controlled by the iron‐BMP–Smad pathway. Overexpressing Smad6, Bambi or Follistatin in cells significantly reduced hepcidin expression. Smad7 functions as a key regulator of iron homoeostasis by negatively controlling hepcidin expression, and Smad6 and Smad7 have non‐redundant roles. Smad6, Bambi and Follistatin serve as additional inhibitors of hepcidin in the liver. |
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| Keywords: |
Bambi
follistatin hepcidin iron deficiency
Smad6
Smad7
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