title: A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv⁻/⁻ mice.
abstract: Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv(-/-) mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv(-/-) mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv(-/-) mice. Notably, steatosis was attenuated in Hjv(-/-) mice on the HFD+Fe regimen. Hjv(-/-) animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of α-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada;
authors.forename: Ranjit Singh
authors.initials: RS
authors.lastname: Padda
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gkouvatsos
authors.affiliation: Department of Diagnostic Sciences and Special Therapies, University of Padova, Padova, Italy; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Guido
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Mui
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: Hojatollah
authors.initials: H
authors.lastname: Vali
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada; kostas.pantopoulos@mcgill.ca.
authors.forename: Kostas
authors.initials: K
authors.lastname: Pantopoulos
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D058851:GPI-Linked Proteins; D005838:Genotype; D006432:Hemochromatosis / Q000150:complications / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000378:metabolism; D007501:Iron / Q000097:blood / Q000378:metabolism*; D058085:Iron Compounds / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012307:Risk Factors; D013997:Time Factors; D015430:Weight Gain
chemical_list: D000199:Actins; D001786:Blood Glucose; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D058085:Iron Compounds; D008565:Membrane Proteins; C544013:alpha-smooth muscle actin, mouse; C515100:iron pentacarbonyl; D002784:Cholesterol; D007501:Iron
keywords: hemochromatosis; iron overload; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis