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

被引:17
作者
Heritage, Mandy L. [2 ,3 ,4 ]
Murphy, Therese L. [2 ,3 ,4 ]
Bridle, Kim R. [2 ,3 ,4 ]
Anderson, Gregory J. [5 ]
Crawford, Darrell H. G. [1 ,2 ,3 ,4 ]
Fletcher, Linda M. [1 ,2 ,3 ,4 ]
机构
[1] Princess Alexandra Hosp, Dept Gastroenterol & Hepatol, Brisbane, Qld 4102, Australia
[2] Univ Queensland, Sch Med, Brisbane, Qld, Australia
[3] Univ Queensland, Gallipoli Res Fdn, Brisbane, Qld, Australia
[4] Greenslopes Hosp, Brisbane, Qld, Australia
[5] Princess Alexandra Hosp, Queensland Inst Med Res, Brisbane, Qld 4102, Australia
关键词
Iron Regulation; Hemochromatosis; Cofactors; Liver Disease; HIF-1; alpha; STAT3; CEBP alpha; Ferroportin; IRON-METABOLISM; OXIDATIVE STRESS; ANTIMICROBIAL PEPTIDE; C/EBP-ALPHA; LIVER; EXPRESSION; HEMOCHROMATOSIS; TRANSCRIPTION; PATHOGENESIS; HOMEOSTASIS;
D O I
10.1111/j.1530-0277.2009.00969.x
中图分类号
R194 [卫生标准、卫生检查、医药管理];
学科分类号
摘要
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-1 alpha) 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-1 alpha 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.
引用
收藏
页码:1391 / 1400
页数:10
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