title: Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overload.
abstract: OBJECTIVE
  Hepcidin is the central regulator of iron homeostasis and altered hepcidin signalling results in both hereditary and acquired iron overload. While the association between iron overload and development of end-stage liver disease is well established, the underlying mechanisms are largely unknown. To improve that, we analysed hepcidin knockout (KO) mice as a model of iron overload-associated liver disease.
  
  
  METHODS
  Hepcidin wild type (WT) and KO mice fed with 3% carbonyl iron-containing diet starting at one month of age were compared to age-matched animals kept on standard chow. Liver histology and serum parameters were used to assess the extent of liver injury and fibrosis. Iron distribution was determined by subcellular fractionation and electron microscopy.
  
  
  RESULTS
  Among mice kept on iron-rich diet, 6 months old hepcidin KO mice (vs. WT) displayed profound hepatic iron overload (3,186 ± 411 vs. 1,045 ± 159 μg/mg tissue, p<0.005), elevated liver enzymes (ALT: KO 128 ± 6, WT 56 ± 5 IU/L, p<0.05), mild hepatic inflammation and hepatocellular apoptosis. Twelve, but not six months old KO mice fed with iron-rich diet developed moderate liver fibrosis. The liver injury was accompanied by a marked lysosomal iron overload and lysosomal fragility with release of cathepsin B into the cytoplasm. Increased p62 levels and autofluorescent iron complexes suggested impaired protein degradation. As a mechanism leading to lysosomal iron overload, the autophagy (lysosomal influx) was increased.
  
  
  CONCLUSIONS
  Hepcidin KO mice represent a novel model of iron overload-related liver diseases and implicate lysosomal injury as a crucial event in iron toxicity.
authors.affiliation: Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
authors.forename: Mariia
authors.initials: M
authors.lastname: Lunova
authors.affiliation: Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Goehring
authors.affiliation: Department of Medicine III and IZKF, University Hospital Aachen, Aachen, Germany.
authors.forename: Deniz
authors.initials: D
authors.lastname: Kuscuoglu
authors.affiliation: Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Mueller
authors.affiliation: Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Central Electron Microscopy Facility, Ulm University, Ulm, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.affiliation: Institut Cochin, INSERM U1016, Université Paris Descartes, Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Deschemin
authors.affiliation: Institut Cochin, INSERM U1016, Université Paris Descartes, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.affiliation: Department of Medicine III and IZKF, University Hospital Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany; Department of Medicine III and IZKF, University Hospital Aachen, Aachen, Germany. Electronic address: pstrnad@ukaachen.de.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000473:pathology / Q000502:physiology; D064451:Hepcidins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D019266:Iron, Dietary / Q000009:adverse effects*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D055370:Lung Injury / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors
chemical_list: D064451:Hepcidins; D019266:Iron, Dietary; D007501:Iron
keywords: Autophagy; Hemochromatosis; Inflammation