Adenine alleviates iron overload by cAMP/PKA mediated hepatic hepcidin in mice.
Adenine alleviates iron overload by cAMP/PKA mediated hepatic hepcidin in mice.
复制标题
腺嘌呤通过 cAMP/PKA 介导的肝铁调素减轻小鼠铁过载
DOI：
10.1002/jcp.26559
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发表时间：
2018-09
影响因子：
5.6
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Zhang Y;Wang X;Wu Q;Wang H;Zhao L;Wang X;Mu M;Xie E;He X;Shao D;Shang Y;Lai Y;Ginzburg Y;Min J;Wang F
血色沉着症在世界范围内非常普遍，并且常常伴随着高发病率和高死亡率。为了更好地控制铁超载，迫切需要安全的替代降铁方法。我们对主要铁调节荷尔蒙--海普西丁调节剂的无偏维生素筛选表明，腺嘌呤(维生素B4)是一种有效的海普西丁激动剂。腺嘌呤可能通过BMP/SMAD途径，显著诱导人细胞株中海普西丁的mRNA水平和启动子活性的激活。在小鼠身上的进一步研究证实了腺嘌呤对海普西丁上调的影响。与正常饮食喂养的小鼠相比，小鼠腺嘌呤饮食补充剂可通过BMP/SMAD途径增加肝组织中海普西丁的表达。值得注意的是，在高铁喂养的小鼠和遗传性血色病小鼠的HFE−/−小鼠中，富含腺嘌呤的饮食显著改善了铁超载并伴随着海普西丁表达的增强。为了进一步验证这一发现，我们选择了BMP的药理抑制剂(LDN193189)。我们发现LDN193189强阻断腺嘌呤诱导的海普西丁。此外，我们通过使用cAMP类似物8 br cAMP和PKA信号的有效抑制剂H89，揭示了cAMP/PKA依赖的轴在激活腺嘌呤诱导的原代肝细胞中的海普西丁表达中的重要作用。这些发现提示腺嘌呤对遗传性血色素沉着症有潜在的治疗作用。
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.
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DOI：
10.1126/science.1176639
发表时间：
2009-08-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Vecchi C;Montosi G;Zhang K;Lamberti I;Duncan SA;Kaufman RJ;Pietrangelo A
通讯作者：
Pietrangelo A
影响因子：
20.3
作者：
Falzacappa, Maria Vittoria Verga;Spasic, Maja Vujic;Muckenthaler, Martina U.
通讯作者：
Muckenthaler, Martina U.
影响因子：
29.4
作者：
Pietrangelo, Antonello
通讯作者：
Pietrangelo, Antonello
DOI：
10.1084/jem.20141514
发表时间：
2015-05-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kim PG;Nakano H;Das PP;Chen MJ;Rowe RG;Chou SS;Ross SJ;Sakamoto KM;Zon LI;Schlaeger TM;Orkin SH;Nakano A;Daley GQ
通讯作者：
Daley GQ
影响因子：
15.9
作者：
Nicolas, G;Chauvet, C;Vaulont, S
通讯作者：
Vaulont, S