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


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.

SUBMITTER: Schaefer B 

PROVIDER: S-EPMC4599680 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Schaefer Benedikt B   Haschka David D   Finkenstedt Armin A   Petersen Britt-Sabina BS   Theurl Igor I   Henninger Benjamin B   Janecke Andreas R AR   Wang Chia-Yu CY   Lin Herbert Y HY   Veits Lothar L   Vogel Wolfgang W   Weiss Günter G   Franke Andre A   Zoller Heinz H  

Human molecular genetics 20150826 21


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  ...[more]

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