Impaired hepcidin expression in alpha-1-antitrypsin deficiency associated with iron overload and progressive liver disease.

Authors:
Benedikt Schaefer, David Haschka, Armin Finkenstedt, Britt-Sabina Petersen, Igor Theurl, Benjamin Henninger, Andreas R Janecke, Chia-Yu Wang, Herbert Y Lin, Lothar Veits, Wolfgang Vogel, Günter Weiss, Andre Franke, Heinz Zoller
Year of publication:
2015
Volume:
-
Issue:
-
Issn:
0964-6906
Journal title abbreviated:
HUM MOL GENET
Journal title long:
Human molecular genetics
Impact factor:
5.985
Abstract:
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.