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Adenine alleviates iron overload by cAMP/PKA mediated hepatic hepcidin in mice
Author(s) -
Zhang Yingqi,
Wang Xudong,
Wu Qian,
Wang Hao,
Zhao Lu,
Wang Xinhui,
Mu Mingdao,
Xie Enjun,
He Xuyan,
Shao Dandan,
Shang Yanna,
Lai Yongrong,
Ginzburg Yelena,
Min Junxia,
Wang Fudi
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26559
Subject(s) - hepcidin , hemochromatosis , hereditary hemochromatosis , smad , endocrinology , ferroportin , medicine , downregulation and upregulation , chemistry , biology , biochemistry , anemia , transforming growth factor , gene
Hemochromatosis is prevalent and often associated with high rates of morbidity and mortality worldwide. The safe alternative iron‐reducing approaches are urgently needed in order to better control iron overload. Our unbiased vitamin screen for modulators of hepcidin, a master iron regulatory hormone, identifies adenine (vitamin B4) as a potent hepcidin agonist. Adenine significantly induced hepcidin mRNA level and promoter activity activation in human cell lines, possibly through BMP/SMAD pathway. Further studies in mice validated the effect of adenine on hepcidin upregulation. Consistently, adenine dietary supplement in mice led to an increase of hepatic hepcidin expression compared with normal diet–fed mice via BMP/SMAD pathway. Notably, adenine‐rich diet significantly ameliorated iron overload accompanied by the enhanced hepcidin expression in both high iron‐fed mice and in Hfe −/− mice, a murine model of hereditary hemochromatosis. To further validate this finding, we selected pharmacological inhibitors against BMP (LDN193189). We found LDN193189 strongly blocked the hepcidin induction by adenine. Moreover, we uncovered an essential role of cAMP/PKA‐dependent axis in triggering adenine‐induced hepcidin expression in primary hepatocytes by using 8 br cAMP, a cAMP analog, and H89, a potent inhibitor for PKA signaling. These findings suggest a potential therapeutic role of adenine for hereditary hemochromatosis.