title: Interstrain differences in the progression of nonalcoholic steatohepatitis to fibrosis in mice are associated with altered hepatic iron metabolism.
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<WSB/EiJ. Mechanistically, down-regulation of IRP1 was linked to an increased expression of microRNAs miR-200a and miR-223, which was negatively correlated with IRP1. The results of this study demonstrate that the interstrain variability in the extent of fibrogenesis was associated with a strain-dependent deregulation of hepatic iron homeostasis.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Shpyleva
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
authors.forename: Marta
authors.initials: M
authors.lastname: Pogribna
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
authors.forename: Christy
authors.initials: C
authors.lastname: Cozart
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Bryant
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
authors.forename: Volodymyr P
authors.initials: VP
authors.lastname: Tryndyak
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Ross
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079. Electronic address: igor.pogribny@fda.hhs.gov.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation; D005494:Folic Acid Deficiency / Q000150:complications / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000098742:Ferroportin; D001052:Apoferritins; D007501:Iron; D035941:Iron Regulatory Protein 1
keywords: IRP1; Iron metabolism; Liver fibrogenesis; Methyl-deficient diet; NAFLD; miR-200a