Schaefer Benedikt, Haschka David, Finkenstedt Armin, Petersen Britt-Sabina, Theurl Igor, Henninger Benjamin, Janecke Andreas R, Wang Chia-Yu, Lin Herbert Y, Veits Lothar, Vogel Wolfgang, Weiss Günter, Franke Andre, Zoller Heinz
Department of Medicine II, Gastroenterology and Hepatology.
Department of Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology.
Hum Mol Genet. 2015 Nov 1;24(21):6254-63. doi: 10.1093/hmg/ddv348. Epub 2015 Aug 26.
Liver disease due to alpha-1-antitrypsin deficiency (A1ATD) is associated with hepatic iron overload in a subgroup of patients. The underlying cause for this association is unknown. The aim of the present study was to define the genetics of this correlation and the effect of alpha-1-antitrypsin (A1AT) on the expression of the iron hormone hepcidin. Full exome and candidate gene sequencing were carried out in a family with A1ATD and hepatic iron overload. Regulation of hepcidin expression by A1AT was studied in primary murine hepatocytes. Cells co-transfected with hemojuvelin (HJV) and matriptase-2 (MT-2) were used as a model to investigate the molecular mechanism of this regulation. Observed familial clustering of hepatic iron overload with A1ATD suggests a genetic cause, but genotypes known to be associated with hemochromatosis were absent. Individuals homozygous for the A1AT Z-allele with environmental or genetic risk factors such as steatosis or heterozygosity for the HAMP non-sense mutation p.Arg59* presented with severe hepatic siderosis. In hepatocytes, A1AT induced hepcidin mRNA expression in a dose-dependent manner. Experiments in overexpressing cells show that A1AT reduces cleavage of the hepcidin inducing bone morphogenetic protein co-receptor HJV via inhibition of the membrane-bound serine protease MT-2. The acute-phase protein A1AT is an inducer of hepcidin expression. Through this mechanism, A1ATD could be a trigger of hepatic iron overload in genetically predisposed individuals or patients with environmental risk factors for hepatic siderosis.
α-1-抗胰蛋白酶缺乏症（A1ATD）所致的肝病在部分患者中与肝脏铁过载相关。这种关联的潜在原因尚不清楚。本研究的目的是确定这种相关性的遗传学特征以及α-1-抗胰蛋白酶（A1AT）对铁调节激素铁调素表达的影响。对一个患有A1ATD和肝脏铁过载的家族进行了全外显子组和候选基因测序。在原代小鼠肝细胞中研究了A1AT对铁调素表达的调节作用。将与血色素沉着症相关蛋白（HJV）和matriptase-2（MT-2）共转染的细胞用作模型来研究这种调节的分子机制。观察到的肝脏铁过载与A1ATD的家族聚集现象提示存在遗传原因，但未发现已知与血色素沉着症相关的基因型。携带A1AT Z等位基因纯合子且伴有环境或遗传风险因素（如脂肪变性或HAMP无义突变p.Arg59*的杂合性）的个体出现严重的肝脏铁沉积。在肝细胞中，A1AT以剂量依赖的方式诱导铁调素mRNA表达。在过表达细胞中的实验表明，A1AT通过抑制膜结合丝氨酸蛋白酶MT-2减少了铁调素诱导性骨形态发生蛋白共受体HJV的裂解。急性期蛋白A1AT是铁调素表达的诱导剂。通过这种机制，A1ATD可能是遗传易感性个体或有肝脏铁沉积环境风险因素的患者发生肝脏铁过载的触发因素。
