Heparanase Overexpression Reduces Hepcidin Expression, Affects Iron Homeostasis and Alters the Response to Inflammation.
Heparanase Overexpression Reduces Hepcidin Expression, Affects Iron Homeostasis and Alters the Response to Inflammation.
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肝素酶的过表达降低了肝素的表达，影响铁稳态并改变对炎症的反应。
DOI：
10.1371/journal.pone.0164183
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Arosio P
中科院分区：
文献类型：
--
作者：
Asperti M;Stuemler T;Poli M;Gryzik M;Lifshitz L;Meyron-Holtz EG;Vlodavsky I;Arosio P
海普西丁是全身性铁利用的关键调节因子，通过控制铁出口蛋白的降解起作用。它主要在肝脏中表达，受铁、炎症、红细胞生成和缺氧的调节。控制其表达的各种因素主要通过Bmp6/SMAD信号通路发挥作用。其中包括外源性肝素，这是一种强大的肝素阻滞剂，其作用机制尚不完全清楚，但可能涉及与结构相似的内源性肝素硫酸盐(HS)的竞争。为了验证这一假说，我们分析了肝素酶、HS降解酶、修饰的海普西丁表达和铁稳态在肝细胞系和转基因小鼠中的过度表达。结果表明，肝素酶在HepG2细胞中的瞬时和稳定过表达导致了海普西丁的表达和Smad5磷酸化的降低。有趣的是，这些克隆还显示了TfR1和铁蛋白水平的变化，这是一种修改的铁稳态的指标。乙酰肝素酶转基因小鼠肝组织中的海普西丁水平较低，血清和肝脏铁含量升高，脾铁含量降低。即使在炎性脂多糖治疗后，海普西丁的表达仍然出人意料地低。乙酰肝素酶过表达对HS结构的修饰影响了海普西丁的表达和铁稳态，这一发现支持HS参与控制海普西丁表达的机制的假说。
Hepcidin is the key regulator of systemic iron availability that acts by controlling the degradation of the iron exporter ferroportin. It is expressed mainly in the liver and regulated by iron, inflammation, erythropoiesis and hypoxia. The various agents that control its expression act mainly via the BMP6/SMAD signaling pathway. Among them are exogenous heparins, which are strong hepcidin repressors with a mechanism of action not fully understood but that may involve the competition with the structurally similar endogenous Heparan Sulfates (HS). To verify this hypothesis, we analyzed how the overexpression of heparanase, the HS degrading enzyme, modified hepcidin expression and iron homeostasis in hepatic cell lines and in transgenic mice. The results showed that transient and stable overexpression of heparanase in HepG2 cells caused a reduction of hepcidin expression and of SMAD5 phosphorylation. Interestingly, the clones showed also altered level of TfR1 and ferritin, indices of a modified iron homeostasis. The heparanase transgenic mice showed a low level of liver hepcidin, an increase of serum and liver iron with a decrease in spleen iron content. The hepcidin expression remained surprisingly low even after treatment with the inflammatory LPS. The finding that modification of HS structure mediated by heparanase overexpression affects hepcidin expression and iron homeostasis supports the hypothesis that HS participate in the mechanisms controlling hepcidin expression.