title: Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice.
abstract: The aim of this study was to determine the effect of iron overload in the development of nonalcoholic steatohepatitis (NASH) in a genetically obese mouse model (Lepr(db/db)). Leptin receptor-deficient mice were fed a normal or an iron-supplemented chow for 8 wk and switched to normal chow for 8 wk. All dietary iron (DI)-fed mice developed hepatic iron overload predominantly in the reticuloendothelial system. Hepatocellular ballooning injury was observed in the livers of 85% of DI mice, relative to 20% of chow-fed Lepr(db/db). Hepatic malonyldialdehyde levels and mRNA levels of antioxidant genes (Nrf2, Gpx1, and Hmox1) were significantly increased in the DI mice. Hepatic mRNA levels of mitochondrial biogenesis regulators Pgc1α, Tfam, Cox4, and Nrf1 were diminished in the DI mice. In addition, gene expression levels of cytokines (Il6, Tnfα) and several innate and adaptive immune cell markers such as Tlr4, Inos, CD11c, CD4, CD8, and Ifnγ were significantly increased in livers of the DI group. Strikingly, Nlrp3, a component of the inflammasome and Il18, a cytokine elicited by inflammasome activation, were significantly upregulated in the livers of DI mice. In addition, RAW 264.7 macrophages loaded with exogenous iron showed significantly higher levels of inflammatory markers (Inos, Tnfα, Mcp1, Tlr4). Thus dietary iron excess leads to hepatic oxidative stress, inflammasome activation, induction of inflammatory and immune mediators, hepatocellular ballooning injury, and therefore NASH in this model. Taken together, these studies indicate a multifactorial role for iron overload in the pathogenesis of NASH in the setting of obesity and metabolic syndrome.
authors.affiliation: Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington;
authors.forename: Priya
authors.initials: P
authors.lastname: Handa
authors.affiliation: Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington;
authors.forename: Vicki
authors.initials: V
authors.lastname: Morgan-Stevenson
authors.affiliation: Benaroya Research Institute, Seattle, Washington;
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Maliken
authors.affiliation: Benaroya Research Institute, Seattle, Washington;
authors.forename: James E
authors.initials: JE
authors.lastname: Nelson
authors.affiliation: Benaroya Research Institute, Seattle, Washington;
authors.forename: Shenna
authors.initials: S
authors.lastname: Washington
authors.affiliation: Intrinsic Life Sciences, La Jolla, California; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Westerman
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.affiliation: Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington; Benaroya Research Institute, Seattle, Washington; kris.kowdley@swedish.org.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000235:genetics; D019190:Iron Overload / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D008315:Malondialdehyde
keywords: hepatocellular ballooning; immune cell activation; inflammasome; iron excess; reticuloendothelial system