title: Strain- and time-dependent alterations in hepatic iron metabolism in a murine model of nonalcoholic steatohepatitis.
abstract: Nonalcoholic steatohepatitis is a common liver disease that is often accompanied by dysregulated iron metabolism. The aim of the study was to test the hypothesis that aberrant iron metabolism in nonalcoholic steatohepatitis is modulated by genetic susceptibility to inflammation and oxidative stress. Hepatic histology and iron content were assessed in 3 inbred strains of mice (C57BL/6, BALB/c, and C3H/HeJ) fed an atherogenic diet (AD). Hepatic expression of genes relevant to iron metabolism, inflammation, and oxidative stress were quantitated by real-time reverse transcription-polymerase chain reaction. At 6 weeks on the AD, histologic injury and induction of inflammatory and oxidative stress-associated gene expression were most pronounced in C57BL/6. At 18 weeks on the AD, these parameters were similar in C57BL/6 and BALB/c. Atherogenic diet-fed C3H/HeJ showed milder responses at both time points. The AD was associated with decreased hepatic iron concentrations in all strains at 6 and 18 weeks. The decrease in hepatic iron concentrations did not correlate with changes in hepcidin expression and was not associated with altered expression of iron transporters. These findings are similar to those observed in models of obesity-induced steatosis and indicate that hepatic steatosis can be associated with depletion of iron stores that is not explained by upregulation of hepcidin expression by inflammation.
  
  
  CONCLUSIONS
  Nonalcoholic steatohepatitis (NASH) is a common liver disease that often accompanies the metabolic syndrome. The latter condition has been linked to iron deficiency and diminished intestinal iron absorption, likely the result of hepcidin upregulation by chronic inflammation. Paradoxically, some NASH patients accumulate excess hepatic iron, which may increase fibrosis and cancer risk. Iron accumulation has been attributed to suppression of hepcidin by oxidative stress. The objective of this study was to investigate the contributions of inflammation and oxidative stress to altered hepatic iron metabolism in a murine model of NASH using inbred strains of mice with differing susceptibilities to injury.
authors.affiliation: Division of Science and Engineering, Penn State Abington, Abington, PA, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Bloomer
authors.affiliation: Division of Comparative Pathology, Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Department of Pathobiology and Population Medicine, Mississippi State University, Starkville, MS, USA.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Division of Gastroenterology-Hepatology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Department of Internal Medicine, Section of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Ottar M
authors.initials: OM
authors.lastname: Bergmann
authors.affiliation: Iowa City Veterans Administration Medical Center, Iowa City, IA, USA.
authors.forename: M Meleah
authors.initials: MM
authors.lastname: Mathahs
authors.affiliation: Iowa City Veterans Administration Medical Center, Iowa City, IA, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Broadhurst
authors.affiliation: Clear Peak LLC, Greenwood Village, CO, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Hicsasmaz
authors.affiliation: Division of Gastroenterology-Hepatology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.|Iowa City Veterans Administration Medical Center, Iowa City, IA, USA.|Program in Free Radical and Radiation Biology, Department of Radiation Oncology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Brown
mesh_terms: D000818:Animals; D001835:Body Weight; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D064451:Hepcidins / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D018384:Oxidative Stress / Q000235:genetics; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D064451:Hepcidins; D012333:RNA, Messenger; D007501:Iron
keywords: H-ferritin; hemosiderosis; hepcidin; inflammation; oxidative stress