title: 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.
authors: Department of Medicine II, Gastroenterology and Hepatology.
authors: Benedikt
authors: B
authors: Schaefer
authors: Department of Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology.
authors: David
authors: D
authors: Haschka
authors: Department of Medicine II, Gastroenterology and Hepatology.
authors: Armin
authors: A
authors: Finkenstedt
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany.
authors: Britt-Sabina
authors: BS
authors: Petersen
authors: Department of Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology.
authors: Igor
authors: I
authors: Theurl
authors: Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors: Benjamin
authors: B
authors: Henninger
authors: Department of Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria, Division of Human Genetics, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors: Andreas R
authors: AR
authors: Janecke
authors: Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA and.
authors: Chia-Yu
authors: CY
authors: Wang
authors: Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA and.
authors: Herbert Y
authors: HY
authors: Lin
authors: Institute of Pathology, Klinikum Bayreuth, Preuschwitzerstraße 101, 95445 Bayreuth, Germany.
authors: Lothar
authors: L
authors: Veits
authors: Department of Medicine II, Gastroenterology and Hepatology.
authors: Wolfgang
authors: W
authors: Vogel
authors: Department of Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology.
authors: Günter
authors: G
authors: Weiss
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany.
authors: Andre
authors: A
authors: Franke
authors: Department of Medicine II, Gastroenterology and Hepatology, heinz.zoller@i-med.ac.at.
authors: Heinz
authors: H
authors: Zoller
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins / Q000096:biosynthesis*; D006801:Humans; D019190:Iron Overload / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012697:Serine Endopeptidases / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D012697:Serine Endopeptidases; C467801:matriptase 2