Interstrain differences in the progression of nonalcoholic steatohepatitis to fibrosis in mice are associated with altered hepatic iron metabolism |
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Affiliation: | 1. Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079;2. Toxicologic Pathology Associates, National Center for Toxicological Research, FDA, Jefferson, AR 72079;3. Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892;1. University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands;2. Dutch Molecular Pathology Center, Department of Pathology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, De Uithof, 3584 CL Utrecht, The Netherlands;3. Department of Molecular Genetics, Maastricht University, 6202 AZ Maastricht, The Netherlands;4. University of Texas Southwestern Medical Center, Departments of Internal Medicine and Molecular Biology, Dallas, TX 75390-9151, USA |
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Abstract: | Nonalcoholic fatty liver disease (NAFLD) is a major health problem worldwide. Currently, there is a lack of conclusive information to clarify the molecular events and mechanisms responsible for the progression of NAFLD to fibrosis and cirrhosis and, more importantly, for differences in interindividual disease severity. The aim of this study was to investigate a role of interindividual differences in iron metabolism among inbred mouse strains in the pathogenesis and severity of fibrosis in a model of NAFLD. Feeding male A/J, 129S1/SvImJ and WSB/EiJ mice a choline- and folate-deficient diet caused NAFLD-associated liver injury and iron metabolism abnormalities, especially in WSB/EiJ mice. NAFLD-associated fibrogenesis was correlated with a marked strain- and injury-dependent increase in the expression of iron metabolism genes, especially transferrin receptor (Tfrc), ferritin heavy chain (Fth1), and solute carrier family 40 (iron-regulated transporter), member 1 (Slc40a1, Fpn1) and their related proteins, and pronounced down-regulation of the iron regulatory protein 1 (IRP1), with the magnitude being A/J<129S1/SvImJ
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