Tangudu Naveen Kumar, Buth Nils, Strnad Pavel, Cirstea Ion C, Spasić Maja Vujić
Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm 89081, Germany.
Department of Medicine III and IZKF, University Hospital Aachen, Aachen 52074, Germany.
Pharmaceuticals (Basel). 2019 May 7;12(2):70. doi: 10.3390/ph12020070.
The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations into the signals that control hepcidin expression, little progress has been made towards investigations into intracellular signaling in the liver under excess of iron. This study examined hepatic signaling pathways underlying acquired and genetic iron overload conditions. Our data demonstrate that hepatic iron overload associates with a decline in the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) kinase (Mek1/2) pathway by selectively affecting the phosphorylation of Erk1/2. We propose that Mek1/2-Erk1/2 signaling is uncoupled from iron-Bmp-Smad-mediated hepcidin induction and that it may contribute to a number of liver pathologies in addition to toxic effects of iron. We believe that our findings will advance the understanding of cellular signaling events in the liver during iron overload of different etiologies.
肝脏通过产生铁调节激素铁调素控制体内铁水平。在包括高度常见的遗传性铁过载疾病在内的许多肝脏疾病中，通常会观察到肝脏铁水平升高和铁调素表达失调。尽管对控制铁调素表达的信号进行了多项突破性研究，但在铁过量情况下对肝脏细胞内信号传导的研究进展甚微。本研究检测了获得性和遗传性铁过载情况下的肝脏信号通路。我们的数据表明，肝脏铁过载与丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（Erk）激酶（Mek1/2）通路激活的下降相关，这是通过选择性影响Erk1/2的磷酸化实现的。我们提出，Mek1/2-Erk1/2信号传导与铁-Bmp-Smad介导的铁调素诱导解偶联，并且除了铁的毒性作用外，它可能还会导致多种肝脏病变。我们相信，我们的研究结果将推动对不同病因铁过载期间肝脏细胞信号传导事件的理解。
