The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice
The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice
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DOI：
10.1172/jci44883
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Muckenthaler, Martina U.
中科院分区：
文献类型：
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作者：
Castoldi, Mirco;Spasic, Maja Vujic;Muckenthaler, Martina U.
全身性铁稳态主要由肝脏通过合成多肽激素海普西丁(HAMP编码)来控制，海普西丁是十二指肠铁吸收和巨噬细胞铁释放的关键调节因子。在这里，我们表明肝脏特异的microRNA miR-122对于调节Hamp mRNA的表达和组织铁水平是重要的。通过在WT小鼠体内注射锁定核酸修饰(LNA修饰)的miR-122抗体，有效和特异地耗尽miR-122会导致全身性铁缺乏，特征是血浆和肝脏铁水平降低，造血功能轻度受损，脾髓外红细胞生成增加。此外，抑制miR-122增加了控制全身铁水平的基因的转录数量，如血色沉着病(HFE)、血凝素(Hjy)、骨形态发生蛋白受体1A型(BMPR1A)和HAMP。重要的是，miR-122直接针对编码海普西丁表达激活子HFE和Hjv的2个mRNAs的3‘非翻译区。这些数据有助于解释miR-122水平降低的小鼠的Hamp mRNA水平升高和随后的铁缺乏，并在miR-122和全身铁代谢调节之间建立了直接的机制联系。
Systemic iron homeostasis is mainly controlled by the liver through synthesis of the peptide hormone hepcidin (encoded by Hamp), the key regulator of duodenal iron absorption and macrophage iron release. Here we show that the liver-specific microRNA miR-122 is important for regulating Hamp mRNA expression and tissue iron levels. Efficient and specific depletion of miR-122 by injection of a locked-nucleic-acid-modified (LNA-modified) anti-miR into WT mice caused systemic iron deficiency, characterized by reduced plasma and liver iron levels, mildly impaired hematopoiesis, and increased extramedullary erythropoiesis in the spleen. Moreover, miR-122 inhibition increased the amount of mRNA transcribed by genes that control systemic iron levels, such as hemochromatosis (Hfe), hemojuvelin (Hjy), bone morphogenetic protein receptor type 1A (Bmpr1a), and Hamp. Importantly, miR-122 directly targeted the 3' untranslated region of 2 mRNAs that encode activators of hepcidin expression, Hfe and Hjv. These data help to explain the increased Hamp mRNA levels and subsequent iron deficiency in mice with reduced miR-122 levels and establish a direct mechanistic link between miR-122 and the regulation of systemic iron metabolism.