{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T01:36:37Z","timestamp":1789868197754,"version":"4.0.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1126,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,8]]},"abstract":"\n \n \n Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n or<\/jats:bold>\n \n Tfr2\n <\/jats:bold>\n , either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n knockout (<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212),<\/jats:bold>\n \n Tfr2\n <\/jats:bold>\n Y245X mutant (<\/jats:bold>\n \n Tfr2\n <\/jats:bold>\n \n mut), and double-mutant (<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212\u00d7<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F2-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction.<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212\u00d7<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212,<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n , and wild-type (WT) mice.<\/jats:bold>\n \n Hamp1\n <\/jats:bold>\n expression was reduced to 40% (<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212 and<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n ) and 1% (<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212\u00d7<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n ) of WT values.<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212 \u00d7<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)\u2013positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition.<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212 and<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n mice had less hepatic inflammation and collagen deposition. Liver F2-isoprostane levels were elevated, and copper\/zinc and manganese SOD activities decreased in<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212\u00d7<\/jats:bold>\n \n Tfr2mut,\n <\/jats:bold>\n \n Tfr2mut, and\n <\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212 mice, compared with WT mice.<\/jats:bold>\n \n Conclusion\n <\/jats:bold>\n : Disruption of both<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n and<\/jats:bold>\n \n Tfr2\n <\/jats:bold>\n caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The<\/jats:bold>\n \n Hfe\n <\/jats:bold>\n \n \u2212\/\u2212\u00d7<\/jats:bold>\n \n Tfr2mut\n \n <\/jats:bold>\n mouse model of iron-induced liver injury reflects the liver injury phenotype observed in human HH. (HEPATOLOGY 2012)<\/jats:bold>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.25689","type":"journal-article","created":{"date-parts":[[2012,3,4]],"date-time":"2012-03-04T01:29:06Z","timestamp":1330824546000},"page":"585-593","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":49,"title":["Disruption of hemochromatosis protein and transferrin receptor 2 causes iron-induced liver injury in mice"],"prefix":"10.1097","volume":"56","author":[{"given":"Roheeth D.","family":"Delima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita C.G.","family":"Chua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janina E.E.","family":"Tirnitz-Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eng K.","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Croft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross M.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"Olynyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"Trinder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-22-20241201","doi-asserted-by":"crossref","first-page":"393408","DOI":"10.1053\/j.gastro.2010.06.013","article-title":"Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.","volume":"139","author":"Pietrangelo","year":"2010","journal-title":"Gastroenterology"},{"key":"R2-22-20241201","doi-asserted-by":"crossref","first-page":"718724","DOI":"10.1056\/NEJM199909023411002","article-title":"A populationbased study of the clinical expression of the hemochromatosis gene.","volume":"341","author":"Olynyk","year":"1999","journal-title":"N Engl J Med"},{"key":"R3-22-20241201","doi-asserted-by":"crossref","first-page":"399408","DOI":"10.1038\/ng0896-399","article-title":"A novel MHC class Ilike gene is mutated in patients with hereditary haemochromatosis.","volume":"13","author":"Feder","year":"1996","journal-title":"Nat Genet"},{"key":"R4-22-20241201","doi-asserted-by":"crossref","first-page":"221230","DOI":"10.1056\/NEJMoa073286","article-title":"Ironoverloadrelated disease in HFE hereditary hemochromatosis.","volume":"358","author":"Allen","year":"2008","journal-title":"N Engl J Med"},{"key":"R5-22-20241201","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1038\/ng1053","article-title":"Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.","volume":"33","author":"Roetto","year":"2003","journal-title":"Nat Genet"},{"key":"R6-22-20241201","doi-asserted-by":"crossref","first-page":"12951302","DOI":"10.1053\/gast.2002.32984","article-title":"Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene.","volume":"122","author":"Girelli","year":"2002","journal-title":"Gastroenterology"},{"key":"R7-22-20241201","doi-asserted-by":"crossref","first-page":"619623","DOI":"10.1172\/JCI200113468","article-title":"Autosomaldominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.","volume":"108","author":"Montosi","year":"2001","journal-title":"J Clin Invest"},{"key":"R8-22-20241201","doi-asserted-by":"crossref","first-page":"9911001","DOI":"10.1002\/hep.22507","article-title":"Hereditary hemochromatosis in the postHFE era.","volume":"48","author":"Olynyk","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R9-22-20241201","doi-asserted-by":"crossref","first-page":"584592","DOI":"10.1016\/S0168-8278(97)80424-2","article-title":"Hepatic stellate cell activation in genetic haemochromatosis. Lobular distribution, effect of increasing hepatic iron, and response to phlebotomy.","volume":"26","author":"Ramm","year":"1997","journal-title":"J Hepatol"},{"key":"R10-22-20241201","doi-asserted-by":"crossref","first-page":"567569","DOI":"10.1111\/j.1572-0241.2001.03472.x","article-title":"Is there a threshold of hepatic iron concentration that leads to cirrhosis in C282Y hemochromatosis?","volume":"96","author":"Adams","year":"2001","journal-title":"Am J Gastroenterol"},{"key":"R11-22-20241201","doi-asserted-by":"crossref","first-page":"545555","DOI":"10.1016\/S0891-5849(97)00284-0","article-title":"Enhanced gammaglutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload.","volume":"24","author":"Brown","year":"1998","journal-title":"Free Radic Biol Med"},{"key":"R12-22-20241201","doi-asserted-by":"crossref","first-page":"36083614","DOI":"10.1182\/blood.V88.9.3608.bloodjournal8893608","article-title":"Oxidative stress and antioxidant status in betathalassemia major: iron overload and depletion of lipidsoluble antioxidants.","volume":"88","author":"Livrea","year":"1996","journal-title":"Blood"},{"key":"R13-22-20241201","doi-asserted-by":"crossref","first-page":"16491655","DOI":"10.1016\/j.freeradbiomed.2007.08.026","article-title":"Elevated F2isoprostanes in thalassemic patients.","volume":"43","author":"Matayatsuk","year":"2007","journal-title":"Free Radic Biol Med"},{"key":"R14-22-20241201","doi-asserted-by":"crossref","first-page":"278283","DOI":"10.1021\/tx00044a013","article-title":"Formation of 1,N6ethenoadenine and 3,N4ethenocytosine by lipid peroxidation products and nucleic acid bases.","volume":"8","author":"el Ghissassi","year":"1995","journal-title":"Chem Res Toxicol"},{"key":"R15-22-20241201","doi-asserted-by":"crossref","first-page":"17331741","DOI":"10.1053\/j.gastro.2003.09.035","article-title":"Cancer risk in patients with hereditary hemochromatosis and in their firstdegree relatives.","volume":"125","author":"Elmberg","year":"2003","journal-title":"Gastroenterology"},{"key":"R16-22-20241201","doi-asserted-by":"crossref","first-page":"613617","DOI":"10.1093\/carcin\/16.3.613","article-title":"1,N6ethenodeoxyadenosine and 3,N4ethenodeoxycytine in liver DNA from humans and untreated rodents detected by immunoaffinity32Ppostlabeling.","volume":"16","author":"Nair","year":"1995","journal-title":"Carcinogenesis"},{"key":"R17-22-20241201","doi-asserted-by":"crossref","first-page":"68936901","DOI":"10.3748\/wjg.14.6893","article-title":"Function of the hemochromatosis protein HFE: lessons from animal models.","volume":"14","author":"Pantopoulos","year":"2008","journal-title":"World J Gastroenterol"},{"key":"R18-22-20241201","doi-asserted-by":"crossref","first-page":"24922497","DOI":"10.1073\/pnas.95.5.2492","article-title":"HFE gene knockout produces mouse model of hereditary hemochromatosis.","volume":"95","author":"Zhou","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R19-22-20241201","doi-asserted-by":"crossref","first-page":"1065310658","DOI":"10.1073\/pnas.162360699","article-title":"Targeted mutagenesis of the murine transferrin receptor2 gene produces hemochromatosis.","volume":"99","author":"Fleming","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R20-22-20241201","doi-asserted-by":"crossref","first-page":"G865G876","DOI":"10.1152\/ajpgi.00150.2011","article-title":"Altered lipid metabolism in Hfeknockout mice promotes severe NAFLD and early fibrosis.","volume":"301","author":"Tan","year":"2011","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R21-22-20241201","doi-asserted-by":"crossref","first-page":"425431","DOI":"10.1016\/j.jhep.2009.12.010","article-title":"Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of haemochromatosis.","volume":"52","author":"Chua","year":"2010","journal-title":"J Hepatol"},{"key":"R22-22-20241201","doi-asserted-by":"crossref","first-page":"15031509","DOI":"10.1182\/blood-2008-03-143354","article-title":"Iron regulates phosphorylation of Smad158 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.","volume":"112","author":"Kautz","year":"2008","journal-title":"Blood"},{"key":"R23-22-20241201","doi-asserted-by":"crossref","first-page":"19071914","DOI":"10.1053\/j.gastro.2011.06.077","article-title":"Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe.","volume":"141","author":"Corradini","year":"2011","journal-title":"Gastroenterology"},{"key":"R24-22-20241201","doi-asserted-by":"crossref","first-page":"G323G328","DOI":"10.1152\/ajpgi.00278.2006","article-title":"Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3.","volume":"292","author":"Drake","year":"2007","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R25-22-20241201","doi-asserted-by":"crossref","first-page":"795799","DOI":"10.1038\/icb.1954.82","article-title":"Studies on intermediary iron metabolism. V. The measurement of nonhaemoglobin tissue iron.","volume":"32","author":"Kaldor","year":"1954","journal-title":"Aust J Exp Biol Med Sci"},{"key":"R26-22-20241201","first-page":"291302","article-title":"Tumor necrosis factorlike weak inducer of apoptosis is a mitogen for liver progenitor cells.","volume":"52","author":"TirnitzParker","year":"2010","journal-title":"HEPATOLOGY"},{"key":"R27-22-20241201","doi-asserted-by":"crossref","first-page":"117125","DOI":"10.1006\/abio.1998.3037","article-title":"An improved method for the measurement of urinary and plasma F2isoprostanes using gas chromatographymass spectrometry.","volume":"268","author":"Mori","year":"1999","journal-title":"Anal Biochem"},{"key":"R28-22-20241201","doi-asserted-by":"crossref","first-page":"19922000","DOI":"10.1002\/hep.23198","article-title":"Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload.","volume":"50","author":"Wallace","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R29-22-20241201","doi-asserted-by":"crossref","first-page":"136147","DOI":"10.1152\/physiolgenomics.00025.2010","article-title":"In silico QTL mapping of basal liver iron levels in inbred mouse strains.","volume":"43","author":"McLachlan","year":"2011","journal-title":"Physiol Genomics"},{"key":"R30-22-20241201","first-page":"239253","article-title":"Pathophysiology of iron toxicity.","volume":"356","author":"Britton","year":"1994","journal-title":"Adv Exp Med Biol"},{"key":"R31-22-20241201","doi-asserted-by":"crossref","first-page":"798804","DOI":"10.1002\/hep.1840110513","article-title":"Liver gene expression during chronic dietary iron overload in rats.","volume":"11","author":"Pietrangelo","year":"1990","journal-title":"HEPATOLOGY"},{"key":"R32-22-20241201","doi-asserted-by":"crossref","first-page":"869879","DOI":"10.1007\/s00726-009-0293-0","article-title":"Mitochondrial damage, cytotoxicity, and apoptosis in ironpotentiated alcoholic liver fibrosis: amelioration by taurine.","volume":"38","author":"Lakshmi Devi","year":"2010","journal-title":"Amino Acids"},{"key":"R33-22-20241201","doi-asserted-by":"crossref","first-page":"10831088","DOI":"10.1002\/hep.1840210430","article-title":"Iron overload facilitates hepatic fibrosis in the rat alcohollowdose carbon tetrachloride model.","volume":"21","author":"Mackinnon","year":"1995","journal-title":"HEPATOLOGY"},{"key":"R34-22-20241201","doi-asserted-by":"crossref","first-page":"185192","DOI":"10.1016\/S0955-3886(00)00087-4","article-title":"The importance of nontransferrin bound iron in disorders of iron metabolism.","volume":"23","author":"Breuer","year":"2000","journal-title":"Transfus Sci"},{"key":"R35-22-20241201","doi-asserted-by":"crossref","first-page":"953962","DOI":"10.7326\/0003-4819-130-12-199906150-00002","article-title":"HFE genotype in patients with hemochromatosis and other liver diseases.","volume":"130","author":"Bacon","year":"1999","journal-title":"Ann Intern Med"},{"key":"R36-22-20241201","doi-asserted-by":"crossref","first-page":"316320","DOI":"10.1097\/00004836-199106000-00013","article-title":"Biochemical liver profile in hemochromatosis. A survey of 100 patients.","volume":"13","author":"Lin","year":"1991","journal-title":"J Clin Gastroenterol"},{"key":"R37-22-20241201","doi-asserted-by":"crossref","first-page":"98108","DOI":"10.2119\/2007-00114.Jouihan","article-title":"Ironmediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis.","volume":"14","author":"Jouihan","year":"2008","journal-title":"Mol Med"},{"key":"R38-22-20241201","doi-asserted-by":"crossref","first-page":"392401","DOI":"10.1055\/s-2005-923311","article-title":"Pathology of hepatic iron overload.","volume":"25","author":"Brunt","year":"2005","journal-title":"Semin Liver Dis"},{"key":"R39-22-20241201","doi-asserted-by":"crossref","first-page":"20502059","DOI":"10.1016\/0016-5085(92)90331-R","article-title":"Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations.","volume":"102","author":"Deugnier","year":"1992","journal-title":"Gastroenterology"},{"key":"R40-22-20241201","doi-asserted-by":"crossref","first-page":"13081316","DOI":"10.1016\/0270-9139(95)90052-7","article-title":"Kupffer cell iron overload induces intercellular adhesion molecule1 expression on hepatocytes in genetic hemochromatosis.","volume":"21","author":"Stal","year":"1995","journal-title":"HEPATOLOGY"},{"key":"R41-22-20241201","doi-asserted-by":"crossref","first-page":"426433","DOI":"10.1016\/S0168-8278(02)00444-0","article-title":"Evidence for a submorphological inflammatory process in the liver in haemochromatosis.","volume":"38","author":"Bridle","year":"2003","journal-title":"J Hepatol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.25689","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201208000-00022","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T14:05:04Z","timestamp":1733061904000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201208000-00022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8]]},"references-count":41,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2012]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.25689","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2012,8]]}}}