title: Resveratrol mediates therapeutic hepatic effects in acquired and genetic murine models of iron-overload.
abstract: OBJECTIVE
  Abnormal iron metabolism and hepatic iron-overload is a major cause of liver injury and in the development of chronic liver diseases. Iron-overload-mediated liver disease leads to end-stage cirrhosis and/or hepatocellular carcinoma.
  
  
  METHODS
  Using a genetic hemochromatosis (hemojuvelin knockout mice) and non-genetic (secondary iron-overload) murine models of hepatic iron-overload, we elucidated the mechanism of hepatic iron injury and the therapeutic effects of resveratrol.
  
  
  RESULTS
  Hepatic iron-overload was associated with hepatosplenomegaly, increased oxidative stress, hepatic fibrosis, and inflammation, and a pro-apoptotic state which was markedly corrected by resveratrol therapy. Importantly our aging studies with the hemojuvelin knockout mice showed advanced liver disease in association with steatosis in the absence of a diabetic state which recapitulates the essential pathological features seen in clinical iron-overload. Chronic hepatic iron-overload showed increased nuclear localization of acetylated Forkhead fox-O-1 (FoxO1) transcription factor whereas resveratrol dietary intervention reversed the acetylation of FoxO1 in association with increased SIRT1 levels which together with its pleotropic antioxidant properties are likely key mechanisms of its therapeutic action. Importantly, resveratrol treatment did not affect the degree of hepatic iron-overload but rather direct protects the liver from iron-mediated injury.
  
  
  CONCLUSIONS
  Our findings illustrate a novel and definitive therapeutic action of resveratrol and represent an economically feasible therapeutic intervention to treat hepatic iron-overload and liver disease.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: DesAulniers
authors.affiliation: Department of Pediatrics and Pharmacology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.|Department of Physiology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000107:Acetylation / Q000187:drug effects*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002908:Chronic Disease; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006432:Hemochromatosis / Q000150:complications / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008107:Liver Diseases / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D018384:Oxidative Stress / Q000187:drug effects*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D013267:Stilbenes; D007501:Iron; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: hepatic fibrosis; inflammation; iron-overload; lipid peroxidation; oxidative stress; resveratrol