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Hepcidin Regulation in Wild-Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol-Induced Hypoxic Response

Authors

  • Mandy L. Heritage,

    1. From the School of Medicine and Gallipoli Research Foundation University of Queensland (MLH, TLM, KRB, DHGC, LMF) and Greenslopes Hospital; The Queensland Institute of Medical Research (GJA), and The Department of Gastroenterology and Hepatology (DHGC, LMF), Princess Alexandra Hospital, Brisbane, Australia.
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  • Therese L. Murphy,

    1. From the School of Medicine and Gallipoli Research Foundation University of Queensland (MLH, TLM, KRB, DHGC, LMF) and Greenslopes Hospital; The Queensland Institute of Medical Research (GJA), and The Department of Gastroenterology and Hepatology (DHGC, LMF), Princess Alexandra Hospital, Brisbane, Australia.
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  • Kim R. Bridle,

    1. From the School of Medicine and Gallipoli Research Foundation University of Queensland (MLH, TLM, KRB, DHGC, LMF) and Greenslopes Hospital; The Queensland Institute of Medical Research (GJA), and The Department of Gastroenterology and Hepatology (DHGC, LMF), Princess Alexandra Hospital, Brisbane, Australia.
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  • Gregory J. Anderson,

    1. From the School of Medicine and Gallipoli Research Foundation University of Queensland (MLH, TLM, KRB, DHGC, LMF) and Greenslopes Hospital; The Queensland Institute of Medical Research (GJA), and The Department of Gastroenterology and Hepatology (DHGC, LMF), Princess Alexandra Hospital, Brisbane, Australia.
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  • Darrell H. G. Crawford,

    1. From the School of Medicine and Gallipoli Research Foundation University of Queensland (MLH, TLM, KRB, DHGC, LMF) and Greenslopes Hospital; The Queensland Institute of Medical Research (GJA), and The Department of Gastroenterology and Hepatology (DHGC, LMF), Princess Alexandra Hospital, Brisbane, Australia.
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  • Linda M. Fletcher

    1. From the School of Medicine and Gallipoli Research Foundation University of Queensland (MLH, TLM, KRB, DHGC, LMF) and Greenslopes Hospital; The Queensland Institute of Medical Research (GJA), and The Department of Gastroenterology and Hepatology (DHGC, LMF), Princess Alexandra Hospital, Brisbane, Australia.
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Reprint requests: Linda M. Fletcher, PhD, Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Ipswich Road, Brisbane, Qld, Australia 4102; Fax: 61-7-3240 5111; E-mail: Lin_Fletcher@health.qld.gov.au

Abstract

Background /Aims:  Expression of Hamp1, the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice (Hfe−/−). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe−/− mice.

Methods: Hfe−/− and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1α) was measured by western blot.

Results: Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe−/− mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1α protein levels were elevated in alcohol-fed wild-type animals compared with controls.

Conclusion:  Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia.

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