Darrell H G Crawford1, Diana G F Ross1, Lesley-Anne Jaskowski1, Leslie J Burke1, Laurence J Britton2, Nick Musgrave3, David Briskey4, Gautam Rishi5, Kim R Bridle1, V Nathan Subramaniam6. 1. Faculty of Medicine, The University of Queensland, Brisbane, Australia; Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Australia. 2. Faculty of Medicine, The University of Queensland, Brisbane, Australia; Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia. 3. Sullivan and Nicolaides Pathology, Greenslopes Private Hospital, Brisbane, Australia. 4. School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, Australia. 5. Hepatogenomics Research Group, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Australia. 6. Faculty of Medicine, The University of Queensland, Brisbane, Australia; Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Australia; The QIMR Berghofer Medical Research Institute, Brisbane, Australia; Hepatogenomics Research Group, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Australia. Electronic address: nathan.subramaniam@qut.edu.au.
Abstract
BACKGROUND & AIMS: Iron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe-/- mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe-/- mice influenced the development of NAFLD. METHODS: Liver histology was assessed in Hfe-/- mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR). RESULTS: Standard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion. CONCLUSIONS: Our results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited.
BACKGROUND & AIMS:Iron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe-/- mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe-/- mice influenced the development of NAFLD. METHODS: Liver histology was assessed in Hfe-/- mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR). RESULTS: Standard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion. CONCLUSIONS: Our results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited.