Bone morphogenetic protein-binding endothelial regulator of liver sinusoidal endothelial cells induces iron overload in a fatty liver mouse model.
Bone morphogenetic protein-binding endothelial regulator of liver sinusoidal endothelial cells induces iron overload in a fatty liver mouse model.
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DOI：
10.1007/s00535-016-1237-6
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发表时间：
2017-03
影响因子：
6.3
通讯作者：
Kohgo Y
中科院分区：
文献类型：
--
作者：
Hasebe T;Tanaka H;Sawada K;Nakajima S;Ohtake T;Fujiya M;Kohgo Y
非酒精性脂肪性肝病（NAFLD）经常伴有铁超载。然而，由于复杂的铁调素调节分子，铁超载的分子机制仍然未知。为了确定与NAFLD相关的铁失调相关的关键分子，我们对肥胖小鼠的肝脏进行了全RNA测序。雄性C57 BL/6小鼠喂食常规或高脂肪饮食16或48周。通过血浆铁、铁蛋白或肝铁含量评价体内铁。使用半导体高通量测序仪通过转录组分析进行全RNA测序。小鼠肝组织或分离的肝细胞和窦内皮细胞用于评估铁调节分子的表达。喂食高脂肪饮食16周的小鼠显示出过量的铁积累。长期暴露于高脂肪饮食增加肝纤维化和肝内铁积累。测序数据的通路分析显示，包括骨形态发生蛋白（BMP）-SMAD信号传导在内的几种炎症通路受到显著影响。测序分析显示2314个基因发生改变，包括hepcidin编码基因Hamp的mRNA表达降低。发现诱导Hamp的铁调素蛋白表达和SMAD磷酸化减少。通过细胞外结合BMP来抑制BMP-SMAD信号传导的BMP结合内皮调节因子（BMPER）的表达在脂肪肝中上调。此外，免疫组织化学和细胞分离分析表明，BMPER主要表达在肝窦内皮细胞（LSECs），而不是肝细胞。LSEC的BMPER分泌抑制肝细胞中的BMP-SMAD信号传导并进一步降低铁调素蛋白表达。这些肝内分子相互作用提示了NAFLD铁超载的新分子基础。本文的在线版本（doi：10.1007/s 00535 -016-1237-6）包含补充材料，可供授权用户使用。
Non-alcoholic fatty liver disease (NAFLD) is frequently accompanied by iron overload. However, because of the complex hepcidin-regulating molecules, the molecular mechanism underlying iron overload remains unknown. To identify the key molecule involved in NAFLD-associated iron dysregulation, we performed whole-RNA sequencing on the livers of obese mice. Male C57BL/6 mice were fed a regular or high-fat diet for 16 or 48 weeks. Internal iron was evaluated by plasma iron, ferritin or hepatic iron content. Whole-RNA sequencing was performed by transcriptome analysis using semiconductor high-throughput sequencer. Mouse liver tissues or isolated hepatocytes and sinusoidal endothelial cells were used to assess the expression of iron-regulating molecules. Mice fed a high-fat diet for 16 weeks showed excess iron accumulation. Longer exposure to a high-fat diet increased hepatic fibrosis and intrahepatic iron accumulation. A pathway analysis of the sequencing data showed that several inflammatory pathways, including bone morphogenetic protein (BMP)–SMAD signaling, were significantly affected. Sequencing analysis showed 2314 altered genes, including decreased mRNA expression of the hepcidin-coding gene Hamp. Hepcidin protein expression and SMAD phosphorylation, which induces Hamp, were found to be reduced. The expression of BMP-binding endothelial regulator (BMPER), which inhibits BMP–SMAD signaling by binding BMP extracellularly, was up-regulated in fatty livers. In addition, immunohistochemical and cell isolation analyses showed that BMPER was primarily expressed in the liver sinusoidal endothelial cells (LSECs) rather than hepatocytes. BMPER secretion by LSECs inhibits BMP–SMAD signaling in hepatocytes and further reduces hepcidin protein expression. These intrahepatic molecular interactions suggest a novel molecular basis of iron overload in NAFLD. The online version of this article (doi:10.1007/s00535-016-1237-6) contains supplementary material, which is available to authorized users.