Biting the iron bullet: endoplasmic reticulum stress adds the pain of hepcidin to chronic liver disease.
Biting the iron bullet: endoplasmic reticulum stress adds the pain of hepcidin to chronic liver disease.
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DOI：
10.1002/hep.23507
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发表时间：
2010-02
期刊：
影响因子：
13.5
通讯作者：
Kowdley, Kris V
中科院分区：
文献类型：
--
作者：
Messner, Donald J;Kowdley, Kris V
海普西丁是一种由肝脏分泌的多肽荷尔蒙，控制着体内铁的稳态。海普西丁的过量生产会导致炎症贫血，而海普西丁的不足则会导致血色素沉着。炎症和铁是已知的海普西丁表达的细胞外刺激因素。我们发现，内质网(ER)应激还可诱导小鼠肝细胞色素的表达，并导致小鼠低铁血症和脾铁滞留。CREBH(cAMP Response Element-Binding Protein H)是一种内质网应激激活转录因子，能结合并反式激活海普西丁启动子。在CREBH基因敲除小鼠中，对外源性毒素或内质网未折叠蛋白积累的海普西丁的诱导是有缺陷的，表明CREBH在内质网应激调节的海普西丁表达中起作用。内质网应激对海普西丁的调节将参与蛋白质质量控制的细胞内反应与先天免疫和铁稳态联系起来。
Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress-regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.