title: The effect of alcohol and hydrogen peroxide on liver hepcidin gene expression in mice lacking antioxidant enzymes, glutathione peroxidase-1 or catalase.
abstract: This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1(-/-)) and catalase (catalase(-/-)) knockout mice. For alcohol studies, 10% ethanol was administered in the drinking water for 7 days. Gpx-1(-/-) displayed significantly higher hepatic H2O2 levels than catalase(-/-) compared to wild-type mice, as measured by 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The basal level of liver hepcidin expression was attenuated in gpx-1(-/-) mice. Alcohol increased H2O2 production in catalase(-/-) and wild-type, but not gpx-1(-/-), mice. Hepcidin expression was inhibited in alcohol-fed catalase(-/-) and wild-type mice. In contrast, alcohol elevated hepcidin expression in gpx-1(-/-) mice. Gpx-1(-/-) mice also displayed higher level of basal liver CHOP protein expression than catalase(-/-) mice. Alcohol induced CHOP and to a lesser extent GRP78/BiP expression, but not XBP1 splicing or binding of CREBH to hepcidin gene promoter, in gpx-1(-/-) mice. The up-regulation of hepatic ATF4 mRNA levels, which was observed in gpx-1(-/-) mice, was attenuated by alcohol. In conclusion, our findings strongly suggest that H2O2 inhibits hepcidin expression in vivo. Synergistic induction of CHOP by alcohol and H2O2, in the absence of gpx-1, stimulates liver hepcidin gene expression by ER stress independent of CREBH.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology/Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, USA. dharrisonfindik@unmc.edu.
authors.forename: Duygu Dee
authors.initials: DD
authors.lastname: Harrison-Findik
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA. sizhao.lu@unmc.edu.
authors.forename: Sizhao
authors.initials: S
authors.lastname: Lu
mesh_terms: D000818:Animals; D002374:Catalase / Q000235:genetics*; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D000431:Ethanol / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D064451:Hepcidins; C000717248:Hspa5 protein, mouse; D051742:Transcription Factor CHOP; D000431:Ethanol; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase