Interstrain differences in the progression of nonalcoholic steatohepatitis to fibrosis in mice are associated with altered hepatic iron metabolism.
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.
['Shpyleva|Svitlana|S|', 'Pogribna|Marta|M|', 'Cozart|Christy|C|', 'Bryant|Matthew S|MS|', 'Muskhelishvili|Levan|L|', 'Tryndyak|Volodymyr P|VP|', 'Ross|Sharon A|SA|', 'Beland|Frederick A|FA|', 'Pogribny|Igor P|IP|']
D000818:Animals D001052:Apoferritins D027682:Cation Transport Proteins D002796:Choline Deficiency D018450:Disease Progression D015536:Down-Regulation D005494:Folic Acid Deficiency D022781:Hepatocytes D007501:Iron D035941:Iron Regulatory Protein 1 D008099:Liver D008103:Liver Cirrhosis D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008815:Mice, Inbred Strains D035683:MicroRNAs D065626:Non-alcoholic Fatty Liver Disease D011990:Receptors, Transferrin
Iron metabolism NAFLD IRP1 miR-200a Liver fibrogenesis Methyl-deficient diet