Mollbrink Annelie, Holmström Petra, Sjöström Mattias, Hultcrantz Rolf, Eriksson Lennart C, Stål Per
Department of Medicine, Karolinska University Hospital Huddinge, Division of Gastroenterology and Hepatology, Stockholm, Sweden.
Scand J Gastroenterol. 2012 May;47(5):591-600. doi: 10.3109/00365521.2012.661761. Epub 2012 Feb 27.
In rat, the first 18-24 h after partial hepatectomy (PH) are characterized by an acute-phase reaction, after which liver regeneration predominates. Interleukin-6 (IL-6) induces the iron hormone hepcidin, which blocks iron uptake and may compromise iron uptake in the growing liver. The expressions of hepcidin and the iron-regulatory pathway of hepcidin gene expression during the late phase of liver regeneration are unknown.
To characterize the expression pattern of hepcidin and the iron-sensing pathway of hepcidin regulation during liver regeneration.
Rats were subjected to PH or sham operation. Liver weights, number of S-phase nuclei, and serum levels of iron and IL-6 were determined. Messenger-RNA levels of hepcidin, ferritin, hemojuvelin, transferrin receptor 1 and 2, HFE, divalent metal transporter 1, ferroportin, and ceruloplasmin were determined with qPCR at different time points. Protein levels of STAT3 and SMAD4 were determined with western blot.
During the acute-phase response, IL-6 release induced STAT3 protein and hepcidin mRNA, whereas mRNA levels of proteins in the iron-sensing pathway (HFE, hemojuvelin, and transferrin receptor 2) decreased. The mRNA levels of proteins involved in cellular iron uptake were increased and cellular iron export unchanged. During liver regeneration >24 h after PH, gene expressions in the iron-sensing pathway were continuously suppressed and hepcidin mRNA levels declined 3-7 days after surgery.
Hepcidin gene expression peaks during the acute-phase response, but a sustained down-regulation of the iron-sensing pathway of hepcidin regulation gradually reduces hepcidin gene expression until regeneration is complete, thereby promoting iron mobilization to the regenerating liver.
在大鼠中，部分肝切除（PH）后的最初18 - 24小时以急性期反应为特征，之后肝再生占主导。白细胞介素-6（IL-6）诱导铁调节激素铁调素，其阻断铁摄取并可能损害生长中肝脏的铁摄取。肝再生后期铁调素的表达及其基因表达的铁调节途径尚不清楚。
明确肝再生过程中铁调素的表达模式及其调节的铁感应途径。
对大鼠进行PH或假手术。测定肝脏重量、S期细胞核数量以及血清铁和IL-6水平。在不同时间点用qPCR测定铁调素、铁蛋白、血色素沉着症相关蛋白、转铁蛋白受体1和2、遗传性血色素沉着症蛋白、二价金属转运体1、铁转运蛋白和铜蓝蛋白的信使核糖核酸水平。用蛋白质印迹法测定信号转导和转录激活因子3（STAT3）和SMAD4的蛋白水平。
在急性期反应期间，IL-6释放诱导STAT3蛋白和铁调素信使核糖核酸，而铁感应途径中的蛋白（遗传性血色素沉着症蛋白、血色素沉着症相关蛋白和转铁蛋白受体2）的信使核糖核酸水平下降。参与细胞铁摄取的蛋白的信使核糖核酸水平升高，细胞铁输出不变。在PH后>24小时的肝再生期间，铁感应途径中的基因表达持续受到抑制，铁调素信使核糖核酸水平在手术后3 - 7天下降。
铁调素基因表达在急性期反应期间达到峰值，但铁调素调节的铁感应途径的持续下调逐渐降低铁调素基因表达，直至再生完成，从而促进铁向再生肝脏的动员。
