title: Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.
abstract: Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model.
authors.affiliation: Gallipoli Medical Research Institute, Greenslopes Private Hospital, Greenslopes, Queensland, Australia The School of Medicine, University of Queensland, Herston, Queensland, Australia The Department of Gastroenterology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia l.britton@uq.edu.au.
authors.forename: Laurence
authors.initials: L
authors.lastname: Britton
authors.affiliation: Gallipoli Medical Research Institute, Greenslopes Private Hospital, Greenslopes, Queensland, Australia The School of Medicine, University of Queensland, Herston, Queensland, Australia QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Lesley
authors.initials: L
authors.lastname: Jaskowski
authors.affiliation: Gallipoli Medical Research Institute, Greenslopes Private Hospital, Greenslopes, Queensland, Australia The School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Bridle
authors.affiliation: Gallipoli Medical Research Institute, Greenslopes Private Hospital, Greenslopes, Queensland, Australia The School of Medicine, University of Queensland, Herston, Queensland, Australia QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Nishreen
authors.initials: N
authors.lastname: Santrampurwala
authors.affiliation: Gallipoli Medical Research Institute, Greenslopes Private Hospital, Greenslopes, Queensland, Australia The School of Medicine, University of Queensland, Herston, Queensland, Australia Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
authors.forename: Janske
authors.initials: J
authors.lastname: Reiling
authors.affiliation: Sullivan and Nicolaides Pathology, Greenslopes Private Hospital, Greenslopes, Queensland, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Musgrave
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
authors.affiliation: Gallipoli Medical Research Institute, Greenslopes Private Hospital, Greenslopes, Queensland, Australia The School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Darrell
authors.initials: D
authors.lastname: Crawford
mesh_terms: D000818:Animals; D002333:Carnitine Acyltransferases / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000378:metabolism; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007501:Iron / Q000378:metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000378:metabolism
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D047493:PPAR alpha; D054419:Receptors, Adiponectin; D007501:Iron; D002333:Carnitine Acyltransferases; D005947:Glucose
keywords: Diabetes; iron; nonalcoholic fatty liver disease; steatohepatitis