Bmp6 expression can be regulated independently of liver iron in mice.
The liver is the primary organ for storing iron and plays a central role in the regulation of body iron levels by secretion of the hormone Hamp1. Although many factors modulate Hamp1 expression, their regulatory mechanisms are poorly understood. Here, we used conditional knockout mice for the iron exporter ferroportin1 (Fpn1) to modulate tissue iron in specific tissues in combination with iron-deficient or iron-rich diets and transferrin (Tf) supplementation to investigate the mechanisms underlying Hamp1 expression. Despite liver iron overload, expression of bone morphogenetic protein 6 (Bmp6), a potent-stimulator of Hamp1 expression that is expressed under iron-loaded conditions, was decreased. We hypothesized that factors other than liver iron must play a role in controlling Bmp6 expression. Our results show that erythropoietin and Tf-bound iron do not underlie the down-regulation of Bmp6 in our mice models. Moreover, Bmp6 was down-regulated under conditions of high iron demand, irrespective of the presence of anemia. We therefore inferred that the signals were driven by high iron demand. Furthermore, we also confirmed previous suggestions that Tf-bound iron regulates Hamp1 expression via Smad1/5/8 phosphorylation without affecting Bmp6 expression, and the effect of Tf-bound iron on Hamp1 regulation appeared before a significant change in Bmp6 expression. Together, these results are consistent with novel mechanisms for regulating Bmp6 and Hamp1 expression.
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China ; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Zhuzhen
Z
Zhang
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China ; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Xin
X
Guo
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
Carolina
C
Herrera
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China ; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Yunlong
Y
Tao
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China ; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Qian
Q
Wu
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China ; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Aimin
A
Wu
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China ; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Hao
H
Wang
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
Thomas B
TB
Bartnikas
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China.
Fudi
F
Wang
D018798:Anemia, Iron-Deficiency / Q000235:genetics / Q000473:pathology; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D064451:Hepcidins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D044967:Serum / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D000098742:Ferroportin
C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D051785:Smad Proteins; D014168:Transferrin; D000098742:Ferroportin; D007501:Iron