In conclusion, our findings strongly suggest that H 2O 2 inhibits hepcidin expression in vivo. The up-regulation of hepatic ATF4 mRNA levels, which was observed in gpx-1 −/− mice, was attenuated by alcohol. 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. Gpx-1 −/− mice also displayed higher level of basal liver CHOP protein expression than catalase −/− mice. In contrast, alcohol elevated hepcidin expression in gpx-1 −/− mice. Hepcidin expression was inhibited in alcohol-fed catalase −/− and wild-type mice. Alcohol increased H 2O 2 production in catalase −/− and wild-type, but not gpx-1 −/−, mice. The basal level of liver hepcidin expression was attenuated in gpx-1 −/− mice. Gpx-1 −/− displayed significantly higher hepatic H 2O 2 levels than catalase −/− compared to wild-type mice, as measured by 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA). For alcohol studies, 10% ethanol was administered in the drinking water for 7 days. This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H 2O 2) in glutathione peroxidase-1 (gpx-1 −/−) and catalase (catalase −/−) knockout mice.
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March 2023
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