Alcohol Activates TGF-Beta but Inhibits BMP Receptor-Mediated Smad Signaling and Smad4 Binding to Hepcidin Promoter in the Liver.
Alcohol Activates TGF-Beta but Inhibits BMP Receptor-Mediated Smad Signaling and Smad4 Binding to Hepcidin Promoter in the Liver.
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DOI：
10.1155/2012/459278
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发表时间：
2012
影响因子：
1.8
通讯作者：
Harrison-Findik DD
中科院分区：
文献类型：
--
作者：
Gerjevic LN;Liu N;Lu S;Harrison-Findik DD
铁调素是铁代谢的关键调节因子，由骨形态发生蛋白（BMP）激活。小鼠配对喂养普通和含乙醇的L。采用De Carli饮食来研究酒精对肝脏中BMP信号传导和铁调素转录的影响。酒精诱导的脂肪变性和TGF-β表达。肝脏BMP 2的表达显著升高，但BMP 4或BMP 6的表达不显著升高。尽管BMP表达增加，但BMP受体和转录因子Smad 1和Smad 5未被激活。相反，酒精刺激Smad 2磷酸化。然而，Smad 4 DNA结合活性和Smad 4与hepcidin启动子的结合减弱。总之，酒精刺激TGF-β和BMP 2的表达，以及Smad 2磷酸化，但抑制BMP受体，以及Smad 1和Smad 5活化。因此，肝脏中的Smad信号通路可能参与酒精对铁调素转录和铁代谢的调节。这些发现有助于进一步了解酒精和铁引起肝损伤的机制。
Hepcidin, a key regulator of iron metabolism, is activated by bone morphogenetic proteins (BMPs). Mice pair-fed with regular and ethanol-containing L. De Carli diets were employed to study the effect of alcohol on BMP signaling and hepcidin transcription in the liver. Alcohol induced steatosis and TGF-beta expression. Liver BMP2, but not BMP4 or BMP6, expression was significantly elevated. Despite increased BMP expression, the BMP receptor, and transcription factors, Smad1 and Smad5, were not activated. In contrast, alcohol stimulated Smad2 phosphorylation. However, Smad4 DNA-binding activity and the binding of Smad4 to hepcidin promoter were attenuated. In summary, alcohol stimulates TGF-beta and BMP2 expression, and Smad2 phosphorylation but inhibits BMP receptor, and Smad1 and Smad5 activation. Smad signaling pathway in the liver may therefore be involved in the regulation of hepcidin transcription and iron metabolism by alcohol. These findings may help to further understand the mechanisms of alcohol and iron-induced liver injury.